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HANDBOOK OF
MEDICINE
The Handbook of Systemic Drug Treatment in Dermatology helps
prescribers and patients make rational decisions about drug treatment
while considering known risks and potential unwanted effects.
Presented in a concise and reader-friendly format, this valuable reference is of practical use for dermatologists at all stages in their careers
as well as specialist nurse practitioners and family practitioners who
share the care of patients being administered systemic dermatological
therapy. It can also be helpful to those in allied specialties such as
rheumatology, gastroenterology, and ophthalmology.
SYSTEMIC DRUG
TREATMENT IN
DERMATOLOGY
S E C O N D
E D I T I O N
This second edition includes new drugs as well as information on new
guidelines for prescribing and monitoring established drugs.
Edited by
Sarah H Wakelin, BSc, MB BS, FRCP, Consultant Dermatologist,
St. Mary’s Hospital, Imperial College Healthcare Trust, and Honorary
Senior Lecturer, Imperial College London, London, UK
Howard I Maibach, MD, Professor, Department of Dermatology,
University of California, San Francisco, San Francisco, CA, USA
Clive B Archer, BSc, MB BS, MSc Med Ed, MD (Lond), PhD, FRCP (Edin,
Glasg, Lond), Consultant Dermatologist, St John’s Institute of Dermatology, Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, and
Visiting Senior Lecturer in Pharmacology, Institute of Pharmaceutical
Science, King’s College London, London, UK
K22298
ISBN: 978-1-4822-2284-5
90000
Sarah H Wakelin | Howard I Maibach | Clive B Archer
9 781482 222845
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HANDBOOK OF
SYSTEMIC DRUG
TREATMENT IN
DERMATOLOGY
Second Edition
Edited by
Sarah H. Wakelin, BSc, MB BS, FRCP
Consultant Dermatologist
St Mary’s Hospital, Imperial College Healthcare Trust,
& Honorary Senior Lecturer, Imperial College London,
London, UK
Howard I. Maibach, MD
Professor, Department of Dermatology
University of California San Francisco,
San Francisco, CA, USA
Clive B. Archer, BSc, MB BS, MSc Med Ed, MD (Lond), PhD, FRCP (Edin, Glasg, Lond)
Consultant Dermatologist
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK
& Visiting Senior Lecturer in Pharmacology
Institute of Pharmaceutical Science
King’s College London,
London, UK
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CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2015 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20150330
International Standard Book Number-13: 978-1-4822-2286-9 (eBook - PDF)
This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the
publisher can accept any legal responsibility or liability for any errors or omissions that may be made.
The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions
of the publishers. The information or guidance contained in this book is intended for use by medical,
scientific or health-care professionals and is provided strictly as a supplement to the medical or other
professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s
instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified.
The reader is strongly urged to consult the relevant national drug formulary and the drug companies’
and device or material manufacturers’ printed instructions, and their websites, before administering
or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate
whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is
the sole responsibility of the medical professional to make his or her own professional judgements, so
as to advise and treat patients appropriately. The authors and publishers have also attempted to trace
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Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
FDA Pregnancy Categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv
Acitretin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Acne Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Alitretinoin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Antiandrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Antibiotics Commonly Used for Skin Infections . . . . . . . . . . . . . . . . . . . . . . . . . 39
Antifungals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Antivirals for Herpes Viruses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Azole Antihelminths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ciclosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clofazimine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Colchicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cyclophosphamide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dapsone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Fumaric Acid Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hydroxycarbamide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Interferons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Intravenous Immunoglobulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Isotretinoin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ivermectin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
109
113
120
124
128
138
147
154
160
166
176
184
194
Methotrexate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mycophenolate Mofetil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Potassium Iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Propranolol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
200
209
215
220
iii
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Contents
Psoralens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rituximab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sulfapyridine & Sulfamethoxypyridazine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thalidomide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tumour Necrosis Factor Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ustekinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Vismodegib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Systemic Therapy in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Systemic Therapy & Liver Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Systemic Therapy & Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
224
233
240
247
254
264
270
275
283
290
Appendices
1 Patient Health Questionnaire for Depression (PHQ-9) . . . . . . . . . . . . . . . .
2 Reading Chart for Use With Antimalarials. . . . . . . . . . . . . . . . . . . . . . . . . .
3 Example of Consent Form to Opt Out of the Mandatory Pregnancy
Prevention Programme. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4 Dermatology Life Quality Index (DLQI). . . . . . . . . . . . . . . . . . . . . . . . . . . . .
295
296
297
298
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
iv
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Preface
Since the first edition of this handbook, dermatological therapy has made a
quantum leap with the advent of biologics for severe psoriasis. Other advances
include a new oral retinoid, oral anticancer therapy and evolving guidelines for
prescribing and monitoring established drugs. Our therapeutic power grows,
but changes in society mean that those taking drugs are increasingly likely
to be elderly, have co-morbidities and to be taking multiple medications – all
factors which increase the risk of adverse effects. Coupled with growing patient
expectations and recourse to litigation, the prescribing physician must carefully
evaluate risks versus benefit and be able to explain these clearly to allow
patients to share in the decisions about their care. Doctors may prescribe any
medicine for any legitimate purpose if they judge it to be in the best interest of
the patient, but if their use is for an indication that is not in the product licence
(off label), they are advised to keep good records should there be the need to
justify their decision at a later date. Much prescribing for children is ‘off label’
because clinical trials are usually conducted in adults and there are insufficient
data on children for the regulatory authorities.
Ideally, prescribing information would list the harmful effects of every
drug, with details of its relation to dose and duration of therapy, preventative
measures (if available) and the chance of its occurrence in the population and
preferably the individual. However, the full extent of such information is not
usually available in daily practice. Rare adverse events are especially difficult to
detect, because of the large study size needed to detect these and the possibility
of uncorrected biases with observational studies. Not only do ‘package inserts’
change with time, but they may differ by country of registration.
We hope that the second edition will prove as practical and popular as the
first, despite some gain in girth with age! We have not attempted to appraise
critically the evidence of effectiveness for different drugs in diseases in order
to keep a concise and easy-to-read format. Prescribers are advised to check
doses in up-to-date formularies and to consult manufacturers for full product
information and details of excipients, for use in rare metabolic diseases such
as porphyria and Lapp lactose galactose deficiency. This edition attempts to
generalize across countries. However, each country may have special aspects of
prescribing that should be considered.
Sarah H. Wakelin
Howard I. Maibach
Clive B. Archer
v
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Acknowledgements
The clinical image on the cover is from the collection of St John’s Institute of
Dermatology, King’s College London School of Medicine, with permission.
The editors and publishers are very grateful to Garrett Coman and Nicholas
Blickenstaff, who acted as Editorial Co-ordinators for the USA input into this
edition.
The editors and publishers are also very grateful to the number of reviewers
in the USA who have commented on the international applicability of the advice
contained in various sections; they are acknowledged at the end of the relevant
sections. However, because of international variations it has not been possible
to include all package information about dosages, so readers are encouraged to
confirm the position in their own territories.
vi
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Contributors
Elaine Agius
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Faisal R. Ali
Salford Royal Hospital & University of
Manchester
Manchester, UK
Iaisha Ali
Imperial College Healthcare Trust
London, UK
Mahreen Ameen
Royal Free London NHS Foundation
Trust
London, UK
Clive B. Archer
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Joey L. Chong
King Edward VII Hospital
Windsor, UK
Leena Chularojanamontri
Salford Royal Hospital & University of
Manchester
Manchester, UK
Marie-Louise Daly
Kings College Hospital
London,UK
Luis Dehesa
University of Texas Health Science
Center
San Antonio, USA
Silja Domm
University Schleswig-Holstein
Kiel, Germany
Veronika Dvorakova
South Infirmary and Victoria
University Hospital
Cork, Ireland
Susannah Baron
East Kent Hospitals University NHS
Foundation Trust
Canterbury, UK
David J. Eedy
Craigavon Area Hospital
Portadown, UK
John Berth-Jones
University Hospital
Coventry, UK
John English
University of Nottingham Hospital
Nottingham, UK
Catherine Borysiewicz
Imperial College Healthcare Trust
London, UK
Louise A. Fearfield
Chelsea and Westminster Hospital &
Royal Marsden Hospital
London, UK
Ekaterina Burova
Bedford Hospital
Bedford, UK
Olga Golberg
University Hospital
Leicester, UK
vii
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Contributors
Mark Goodfield
Chapel Allerton Hospital
Leeds, UK
Clive E. Grattan
Norfolk and Norwich University
Hospital & St John’s Institute of
Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Malcolm W. Greaves
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Francisco Kerdel
Florida Academic Dermatology
Centers
Miami, USA
Peter C. M. van de Kerkhof
Radboud University Nijmegen
Medical Centre
Nijmegen, The Netherlands
Murtaza Khan
University Hospital
Coventry, UK
Alison Layton
Harrogate Hospital
Harrogate, UK
Christopher E.M. Griffiths
Salford Royal Hospital & University of
Manchester
Manchester, UK
John T. Lear
Salford Royal Hospital & University of
Manchester
Manchester, UK
Richard W. Groves
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Eglantine Lebas
Centre Hospitalier Universitaire de
Liège
Liège, Belgium
Catherine Hardman
Imperial College Healthcare Trust
London, UK
Karen Harman
University Hospital
Leicester, UK
Roderick J. Hay
King’s College Hospital
London, UK
Victoria J. Hogarth
King’s College Hospital
London, UK
Jonathan Leonard
Imperial College Healthcare Trust
London, UK
Tabi A. Leslie
Royal Free London &
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Hui Min Liew
King’s College Hospital
London, UK
viii
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Contributors
Rose Mak
Imperial College Healthcare Trust
London, UK
Phil Mason
Oxford Kidney Unit
The Churchill Hospital
Oxford, UK
Eirini Mereki
Imperial College Healthcare Trust
London, UK
Rachael Morris-Jones
King’s College Hospital
London, UK
Ulrich Mrowietz
University Schleswig-Holstein
Kiel, Germany
Gillian Murphy
Beaumont Hospital
Dublin, Ireland
Alexander Nast
Charité-Universitätsmedizin
Berlin, Germany
Kristian Reich
Dermatologikum Hamburg
Hamburg and Georg-August
University
Gottingen, Germany
Sara Ritchie
Hospital for Tropical Diseases
University College Hospital
London, UK
Melissa Saber
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Robert P.E. Sarkany
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals
London, UK
Jane Setterfield
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Brid O’Donnell
Mater Misericordiae University
Hospital
Dublin, Ireland
Catherine Smith
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Genevieve Osborne
Imperial College Healthcare Trust
London, UK
Mary Sommerlad
King’s College Hospital
London, UK
Anand Patel
University of Nottingham Hospital
Nottingham, UK
Mark Thursz
Imperial College Healthcare Trust
London, UK
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Contributors
Francisco Vega-Lopez
Hospital for Tropical Diseases
University College Hospital
London, UK
Sarah H. Wakelin
Imperial College Healthcare Trust
London, UK
Stephen L. Walker
Faculty of Infectious and Tropical
Diseases
London School of Hygiene and
Tropical Medicine
London, UK
Rachel Westbrook
King’s College Hospital London
London, UK
Richard Woolf
King’s College London &
St John’s Institute of Dermatology
Guy’s and St Thomas’ Hospitals NHS
Foundation Trust
London, UK
Shirin Zaheri
Imperial College Healthcare Trust
London, UK
Ricardo N. Werner
Charité-Universitätsmedizin
Berlin, Germany
x
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Abbreviations
5-HT 5-hydroxytryptamine
ACE angiotensin converting enzyme
ACTH adrenocorticotrophic hormone
AGEP acute generalized
exanthematous pustulosis
AIDS acquired immunodeficiency
syndrome
ALP alkaline phosphatase
ALT alanine aminotransferase
ANA antinuclear antibodies
(p)ANCA (perinuclear) antineutrophil
cytoplasmic antibody
AST aspartate aminotransferase
AV atrioventricular
BAD British Association of
Dermatologists
BCC basal cell carcinoma
BCG bacillus Calmette–Guérin
bd twice daily, every 12 hours
BMD bone mineral density
BMI body mass index
BNF British National Formulary
BP blood pressure
BSA body surface area
CBC complete blood count (= FBC)
CBG cortisol binding globulin
CIN cervical intraepithelial neoplasia
CK creatine kinase
CKD chronic kidney disease
CMV cytomegalovirus
CNS central nervous system
CS glucocorticosteroids
CSM (UK) Committee for Safety of
Medicines
CTCL cutaneous T-cell lymphoma
CXR chest radiograph
CYP450 cytochrome P450
DCP dexamethasone–
cyclophosphamide pulse
DEXA dual energy X-ray
absorptiometry
DHT dihydrotestosterone
DILI drug induced liver injury
DISH diffuse idiopathic skeletal
hyperostosis
DLE discoid lupus erythematosus
DLQI Dermatology Life Quality Index
DNA deoxyribonucleic acid
DRESS drug reaction (or rash) with
eosinophilia and systemic symptoms
DVT deep venous thrombosis
EBV Epstein–Barr virus
ECG electrocardiogram
ELISA enzyme linked immunosorbent
assay
EMA European Medicines Association
ENL erythema nodosum leprosum
FBC full blood count (= CBC)
FDA (USA) Food and Drug
Administration
FSH follicle stimulating hormone
G6PD glucose-6-phosphate
dehydrogenase
G-CSF granulocyte colony stimulating
factor
(e)GFR (estimated) glomerular
filtration rate
GGT gamma-glutamyl transferase
GI gastrointestinal
GnRH gonadotrophin releasing
hormone
GSH glutathione
HAART highly active antiretroviral
therapy
HBV hepatitis B virus
HCV hepatitis C virus
HDL high-density lipoprotein
HIV human immunodeficiency virus
xi
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Abbreviations
HR heart rate
HRT hormone replacement therapy
HSV herpes simplex virus
IBD inflammatory bowel disease
IFN interferon
Ig immunoglobulin
IGRA interferon-gamma release assay
IL interleukin
i/m intramuscular, intramuscularly
INR international normalized ratio
ITP idiopathic (immune)
thrombocytopenic purpura
i/v intravenous, intravenously
IVF in vitro fertilization
KS Kaposi’s sarcoma
LDL low-density lipoprotein
LE lupus erythematosus
LFT liver function test
LH luteinizing hormone
MAOI monoamine oxidase
inhibibitor
MCV mean corpuscular volume
MF mycosis fungoides
MHRA (UK) Medicines and
Healthcare Products Regulatory
Agency
MI myocardial infarction
MMR mumps, measles, rubella
MPD minimal phototoxic dose
MRI magnetic resonance imaging
(CA/HA)-MRSA (community-acquired/
hospital-acquired) methicillinresistant Staphylococcus aureus
MTX methotrexate
NHL non-Hodgkin’s lymphoma
NICE (UK) National Institute for
Health and Care Excellence
nocte at night
NMSC non-melanoma skin cancer
NRTI nucleoside reverse transcriptase
inhibitor
NSAID non-steroidal antiinflammatory drug
NYHA New York Heart Association
OCP oral contraceptive pill
od once daily, every 24 hours
PIIINP pro-collagen III peptides
PABA para-aminobenzoic acid
PASI Psoriasis Area and Severity Index
PE pulmonary embolism
PGA Physician’s Global Assessment
PML progressive multifocal
leukoencephalopathy
PPP Pregnancy Prevention
Programme
PSA prostate specific antigen
PT prothrombin time
PTC pseudotumour cerebri
PUVA psoralen combined with
ultraviolet A
PVL Panton–Valentine leukocidin
qds four times daily, every 6 hours
RAR retinoic acid receptor
RePUVA PUVA with oral retinoid
therapy
RNA ribonucleic acid
RXR retinoid X receptor
s/c subcutaneous, subcutaneously
SCC squamous cell carcinoma
SHBG sex hormone binding globulin
SLE systemic lupus erythematosus
SPC Summary of Product
Characteristic
SSRI selective serotonin reuptake
inhibitor
STAT signal transducer and activator
of transcription
TB tuberculosis
xii
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Abbreviations
tds three times daily, every 8 hours
TEN toxic epidermal necrolysis
TFT thyroid function test
TGF-b transforming growth factorbeta
TPMT thiopurine methyltransferase
TSH thyroid stimulating hormone
UVA ultraviolet A
UVB ultraviolet B
VTE venous thromboembolism
VZIG varicella/zoster immunoglobulin
VZV varicella zoster virus
WBC white blood cell count
WHO World Health Organization
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FDA Pregnancy Categories
Category A
Adequate and well-controlled studies have failed to
demonstrate a risk to the fetus in the first trimester of
pregnancy (and there is no evidence of risk in later trimesters).
Category B
Animal reproduction studies have failed to demonstrate a risk
to the fetus and there are no adequate and well-controlled
studies in pregnant women.
Category C
Animal reproduction studies have shown an adverse effect
on the fetus and there are no adequate and well-controlled
studies in humans, but potential benefits may warrant use of
the drug in pregnant women despite potential risks.
Category D
There is positive evidence of human fetal risk based on adverse
reaction data from investigational or marketing experience or
studies in humans, but potential benefits may warrant use of
the drug in pregnant women despite potential risks.
Category X
Studies in animals or humans have demonstrated fetal
abnormalities and/or there is positive evidence of human fetal
risk based on adverse reaction data from investigational or
marketing experience, and the risks involved in use of the drug
in pregnant women clearly outweigh potential benefits.
xiv
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Acitretin
Peter C.M. van de Kerkhof
++Classification & mode of action
By the 1960s, modifications of vitamin A (figure 1) resulted in the discovery
of the first generation retinoids, all-trans-retinoic acid and 13-cis-retinoic acid.
Further research led to development of the second generation of retinoids,
the monoaromatic retinoids, etretinate and its metabolite, acitretin. Etretinate
(which is no longer available) and acitretin are effective treatments for psoriasis
and severe congenital disorders of keratinization.
A major problem with systemic retinoids is their teratogenicity, and
separation of this from their therapeutic effects has never been achieved.
Acitretin has a much shorter half-life than etretinate, but a long duration
of pregnancy avoidance post-treatment is still advised, as it transpires that
acitretin can be converted to etretinate in the presence of alcohol, and the
latter is stored in fat with a half-life of 120 days.
Acitretin is an established treatment for psoriasis and, despite development
of biological agents (the biologics), it remains an important therapy due to
its unique mode of action. It binds receptors belonging to the steroid–thyroid
receptor superfamily. Subsequently, the ligand/receptor complex binds to
specific gene regulatory regions to modulate gene expression. Acitretin
has antiproliferative and anti-inflammatory properties. In the epidermis,
acitretin reduces keratinocyte proliferation and normalizes differentiation
and cornification. It also inhibits production of vascular endothelial growth
factor and inhibits intraepidermal neutrophil migration. Acitretin inhibits
interleukin (IL)-6-driven induction of Th17 cells, which play a pivotal role in the
pathogenesis of psoriasis and promote the differentiation of T-regulatory cells.
Unlike other psoriasis therapies, acitretin lacks immunosuppressive effects
and this can be useful in patients with a history of internal malignancy, those
with a history of skin cancer or severe sun damage, transplant recipients
and those with underlying infections such as human immunodeficiency virus
(HIV) infection. In addition, there is emerging evidence that acitretin may be
successfully combined with biologics.
Retinyl ester
Storage
Retinol
Retinal
Retinoic acid (tretinoin)
Active forms
FIGURE 1 Simplified diagram to illustrate the three main active forms of vitamin A
and a storage form.
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Acitretin
++Indications & dermatological uses
The licensed indications for acitretin are as follows:
• Severe extensive psoriasis that cannot be managed by topical treatment or
phototherapy.
• Palmoplantar pustular psoriasis.
• Severe Darier’s disease.
• Severe congenital ichthyosis.
Monotherapy is indicated for erythrodermic or pustular psoriasis while
combination therapy (with phototherapy) is often used for chronic plaque
psoriasis. The efficacy of acitretin monotherapy in chronic plaque psoriasis is
limited and dose dependent, with approximately 70% of patients achieving a
moderate or greater response. Various studies have reported partial clearance
rates of 25–75% with daily doses of 30–40 mg. Lower doses (10 mg or 25 mg
daily) have little therapeutic effect, whereas doses of 50 mg and 75 mg
daily result in an improvement of at least 75% (PASI 75) in 25% of patients.
Complete clearance is rare and adherence at high dosage is often limited by
side-effects.
The comparative efficacy of acitretin monotherapy in chronic plaque
psoriasis is less than methotrexate and ciclosporin (cyclosporine). However,
acitretin in combination with phototherapy (ultraviolet B [UVB] or psoralen
combined with ultraviolet A [PUVA]) has an efficacy at least comparable
with the other non-biologic systemic treatments. An additional advantage of
combination treatment is that lower doses of acitretin and lower cumulative
doses of UVA or UVB can be used. Topical therapy such as calcipotriol should be
continued with acitretin as it may enable increased efficacy at lower dosage.
There is preliminary evidence for improved efficacy in combination therapy
with the antidiabetic drug pioglitazone, although further studies are needed.
There is also limited evidence for the effective combination of acitretin with
etanercept and with hydroxycarbamide (hydroxyurea).
As monotherapy, acitretin is highly effective in erythrodermic and pustular
psoriasis. However, its efficacy in nail psoriasis and psoriatic arthritis is only modest.
Another potential therapeutic use of acitretin is the prophylaxis of nonmelanoma skin cancer in organ transplant recipients. Acitretin may
be considered a first-line systemic therapy for pityriasis rubra pilaris and
lichen planus (especially the hyperkeratotic and erosive variants). Acitretin
has similar efficacy to antimalarials in the treatment of cutaneous lupus
erythematosus.
++Formulations/Presentation
Branded formulations exist with capsule sizes containing 10 mg and 25 mg of
acitretin.
In the USA, there are additional formulations containing 17.5 mg and
22.5 mg acitretin.
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Acitretin
++Dosages & suggested regimens
The recommended starting dose is 25–30 mg or 0.5 mg/kg once daily for chronic
plaque psoriasis, with dose adjustment after 2–4 weeks according to clinical
response and side-effects. A lower starting dose of 0.25 mg/kg is advisable in
erythrodermic psoriasis. For pustular psoriasis, the dose should be escalated up
to the maximum maintenance dose of 75 mg or 1 mg/kg daily. An initial flare
of plaque psoriasis may occur, but improvement is usually evident by 4 weeks.
Optimal response may take over 3 months.
Lower starting doses of 10 mg daily are indicated for Darier’s disease,
with maintenance doses of 10–25 mg daily. Similar low doses can be used in
conjunction with phototherapy.
Acitretin should be taken with or after a fat-containing meal to maximize
bioavailability.
++Baseline investigations & considerations
•
•
•
•
•
•
Pregnancy testing.
Establishment of highly effective contraception.
Full blood count (FBC) (complete blood count [CBC]).
Liver function tests (LFTs).
Serum urea, electrolytes and creatinine.
Fasting lipids and glucose.
++Monitoring
• Pregnancy testing (throughout and beyond treatment in females of
reproductive age).
• Fasting lipids and LFTs monthly for the first 2 months then every 3–6 months.
• Fasting glucose if evidence of impaired glucose tolerance.
• Monitor for development of hyperostosis by history (twice yearly) and by
skeletal x-ray if symptomatic.
• Growth charts for height and weight in those under 18 years.
++Contraindications & cautions
The following are contraindications to systemic retinoid therapy:
• Pregnancy (see below).
• Lactation.
• Uncontrolled severe hyperlipidaemia.
• Hypersensitivity to retinoids or excipients.
Patients taking acitretin should not donate blood during treatment and for 3
years after stopping therapy.
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Acitretin
Extra caution should be taken when acitretin is prescribed in the following:
• Liver dysfunction.
• Severe renal dysfunction (elimination reduced).
• Hyperlipidaemia.
• Alcohol dependency.
• History of pancreatitis.
• Diabetes (glucose tolerance may be impaired).
• Obesity.
• Arteriosclerosis.
• Contact lens use.
• Serious disorders of the retina.
++Important drug interactions
• Ciclosporin (cyclosporine) metabolism: may be inhibited by acitretin as
both drugs are metabolized by the same cytochrome P450 (CYP450) system,
leading to a risk of ciclosporin toxicity.
• Glibenclamide: acitretin enhances the hypoglycaemic effect of glibenclamide.
• Methotrexate and acitretin: have been used successfully as combination
therapy in those patients in whom all other psoriasis treatments have failed.
However, severe hepatotoxicity has been reported, so careful monitoring is
mandatory. As methotrexate itself causes hepatotoxicity it is unclear what
role, if any, acitretin plays in hepatotoxicity.
• Oral contraceptive pill (OCP): there is an additive effect on the elevation of
serum triglycerides and cholesterol but there is no effect on the antiovulatory
action of the combined OCP.
• Phenytoin: protein binding is reduced by acitretin but the clinical significance
of this is unknown.
• Tetracyclines: should be avoided during acitretin therapy as both drugs can
cause benign intracranial hypertension; the risk may be increased if they are
used concurrently.
• Vitamin A: intake should not exceed the recommended dietary allowance
(4,000–5,000 units/d) so supplements should be avoided.
• Alcohol: promotes the esterification of acitretin to etretinate (‘back
metabolism’), which is far more slowly eliminated. This may prolong the risk
of teratogenicity in females of childbearing age.
++Adverse effects & their management
• Teratogenicity is the principal problem with all systemic retinoids. Both
natural forms of vitamin A in high dose (but not its pro-vitamin, betacarotene) and synthetic retinoids are highly teratogenic. Teratogenic effects
include cardiac defects, microcephaly, spina bifida and limb defects. Females
of childbearing potential with a desire to have children should not be given
acitretin due to its long half-life.
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Acitretin
• Hyperlipidaemia is a concern with long-term therapy. Triglycerides and
cholesterol rise during acitretin treatment in about 30% of patients, with
an increase in the low-density lipoprotein (LDL) to high-density lipoprotein
(HDL) ratio (atherogenic index). This occurs particularly in patients with
risk factors for hyperlipidaemia, i.e. excessive alcohol intake, diabetes
mellitus, obesity or a family history of hyperlipidaemia. The elevation is
dose related and can be managed by dietary control, dose reduction or, in
some circumstances, by lipid lowering drugs. If the cholesterol cannot be
maintained below 8.5 mmol/L and the triglyceride level below 3.0 mmol/L,
treatment should be discontinued.
• Hepatitis: a transient modest rise in liver transaminases is common but acute
hepatitis and jaundice are rare. Elevation of liver enzymes above 2–3 times
the upper limit of normal should lead to discontinuation of treatment. If the
elevation of liver enzymes is less than twice the upper limit of normal, the
patient can be managed by more frequent monitoring, e.g. every 2 weeks.
• Mucocutaneous: in view of the commonly occurring dryness or erosions of
the skin and mucous membranes, topical emollients and lip salves should
be used routinely. Scaling, dryness, thinning and erythema may also be
seen, particularly on the face and palmoplantar skin. Rarer cutaneous
manifestations include skin fragility, photosensitivity and development of
excessive granulation tissue. Epistaxis may occur occasionally. Petrolatum
can be smeared into the nostrils to alleviate dryness.
• Hair loss is dose dependent and occurs in up to 75% of patients receiving
acitretin, but only a minority are severely affected. Hair loss diminishes
over time and is usually reversible within 6 months of discontinuation.
Development of curly hair has been reported as a rare effect.
• Ocular adverse effects include sore eyes and decreased tolerance of contact
lenses, which can be alleviated using eye drops (‘artificial tears’). A decrease
in night vision has occasionally been reported.
• Musculoskeletal adverse effects include arthralgia and myalgia, which are
usually mild but may result in reduced exercise tolerance. Long-term (>2
years) treatment with second-generation retinoids has been associated
with an increased risk of calcification of extraspinal tendons and ligaments,
especially ankles, pelvis and knees, and diffuse idiopathic skeletal hyperostosis
(DISH)-like changes in the spine. However, this is not clearly correlated with
dose or duration. Routine monitoring with x-rays is therefore not justifiable
in asymptomatic patients, but targeted radiography may be indicated for
atypical musculoskeletal pain.
• Premature epiphyseal closure can occur in children. In view of the effect of
retinoids on the growth plates there is a potential risk of decreased growth.
However, it is advisable to monitor growth at regular intervals in children
who are treated with acitretin.
• Neurological: headache, drowsiness and benign intracranial hypertension
have occasionally been reported. Subclinical dysfunction of sensory nerve
fibres has been detected after 1 month’s treatment. Taste disturbance may
occur.
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Acitretin
• Systemic: non-specific symptoms such as nausea, malaise or sweating can
sometimes occur.
++Use in special situations
Pregnancy (FDA Category X)
Acitretin is absolutely contraindicated in pregnancy and females should not
become pregnant for at least 3 years after stopping treatment. This duration
is recommended by the British Association of Dermatologists (BAD), FDA and
BNF recommend a 3 year time interval. Pregnancy must be excluded prior to
commencing therapy. Females of childbearing age should have a negative
pregnancy test not more than 2 weeks before starting acitretin.
Highly effective contraception must be used for 1 month prior to, during
and for at least 3 years after cessation of treatment, even in those with a
history of infertility. Precise recommendations will differ between countries.
Acitretin therapy should begin on the second or third day of the menstrual
cycle.
The patient must be able to understand the risks of acitretin treatment,
the consequences of a pregnancy and be able to comply with effective
contraception. Information on how to obtain emergency contraception may
be provided.
There is no evidence of impaired fertility or mutagenic risk in males who
receive acitretin.
Lactation
Acitretin is excreted in breast milk and mothers taking this medication should
not breastfeed.
Children
Acitretin may be used in carefully selected cases under expert supervision,
e.g. in severe ichthyosis. The main concern in this age group is the risk of
premature epiphyseal closure, though it is not clear if this is relevant with lowdose acitretin. Doses of 0.5–1.0 mg/kg/d may be used, up to a maximum of 35
mg/d, but the maintenance dose should be kept as low as possible. In female
children approaching menarche, use of acitretin should be critically reviewed.
++Essential patient information
Patients should be warned of the possible side-effects and given an up-to-date
Drug Information Leaflet as provided by the manufacturer.
Females should avoid pregnancy throughout treatment and for at least
3 years after stopping taking acitretin. Females of childbearing age should sign
an acknowledgement form regarding the risks associated with pregnancy.
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Acitretin
Patients should not donate blood during or for at least 3 years after
treatment. They should avoid tetracyclines, keratolytics, excessive sun exposure
and ultraviolet lamps and supplements of vitamin A.
Wax epilation should be avoided due to the risk of increased skin fragility.
With acknowledgements to Alun V Evans and WAD Griffiths, authors of this
chapter in the 1st edition, and to Steven Feldman who reviewed this chapter
from an international perspective.
++Further reading
Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC. A systematic
review of treatments for severe psoriasis. Health Technol Assess 2000;4(40):
25–49.
Gupta AK, Goldfarb MT, Ellis CN, Voorhees JJ. Side-effect profile of acitretin
therapy in psoriasis. J Am Acad Dermatol 1989;20:1088–93.
Jessop S, Whitelaw DA, Delamere FM. Drugs for discoid lupus erythematosus.
Cochrane Database Syst Rev 2009;4:CD002954.
Menon K, Van Voorhees AS, Bebo B, et al. Psoriasis in patients with HIV
infection: from the Medical Board of the National Psoriasis Foundation. J Am
Acad Dermatol 2010;62:291–9.
Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell
differentiation mediated by retinoic acid. Science 2007;317:256–60.
Ormerod AD, Campalani E, Goodfield MJD. British Association of Dermatologists
Guidelines on the efficacy and use of acitretin in dermatology. Br J Dermatol
2010;162:952–63.
Pathirana D, Ormerod AD, Saiag P, et al. European S3 – Guidelines on the systemic
treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009:23(Suppl. 2):
1–70.
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Acne Antibiotics
Alexander Nast & Ricardo N. Werner
++Classification & mode of action
Certain antibiotics are widely prescribed in the treatment of acne. They decrease
the number and function of Propionibacteria acnes on the surface of the skin
and in the pilosebaceous duct. Tetracyclines and macrolides exert broadspectrum antibacterial effects by inhibiting bacterial protein biosynthesis,
while trimethoprim inhibits bacterial folic acid metabolism. Additional nonantimicrobial actions may be of importance including anti-inflammatory and
antioxidative effects on neutrophils, impairment of matrix metalloproteinase
activity and inhibition of pro-inflammatory cytokines such as IL-1α and TNFα.
These actions are evident at subantimicrobial doses.
++Indications & dermatological uses
The use of systemic antibiotics for the treatment of acne is indicated in the
following:
• Widespread mild-to-moderate papulopustular (inflammatory) acne.
• Severe papulopustular/moderate nodular acne.
• Severe nodular/conglobate acne (as an alternative to oral isotretinoin).
Topical antiacne therapy with a retinoid and/or benzoyl peroxide or azelaic
acid should also be continued in all the above situations.
++Formulations/Presentation
These include the following:
• Doxycycline: 40 mg, 50 mg, 100 mg capsules; 100 mg dispersible tablets.
• Lymecycline: 408 mg capsules.
• Minocycline: 50 mg, 100 mg tablets and capsules.
• Tetracycline and oxytetracycline: 250 mg tablets.
• Erythromycin: 250 mg, 500 mg tablets and capsules; 125 mg/5 ml suspensions
(including sugar-free suspensions).
• Trimethoprim: 100 mg, 200 mg tablets; 50 mg/5 ml suspension.
Erythromycin is formulated as erythromycin base, estolate, ethyl succinate
and stearate.
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Acne antibiotics
++Dosages & suggested regimens
Antibiotics work relatively slowly in acne and it may improve adherence if
patients are advised accordingly. The initial duration of therapy is 2–3 months.
If there is no improvement after this time, another drug should be considered.
Maximum improvement does not usually occur until after 4–6 months. In
more severe cases, oral medication may need to be continued for 2 years or
more. As acne is a chronic complaint, once inflammatory lesions have resolved,
maintenance topical treatment should be prescribed (retinoids and/or benzoyl
peroxide or azelaic acid).
• First choice treatment:
• Doxycycline: 100 mg once daily. (or 50mg–200mg daily)
• Lymecycline: 408 mg once daily.
• Tetracycline and oxytetracycline: 500 mg twice daily.
• Second choice treatment:
• Minocycline: 100 mg once daily.
• Third choice treatment:
• Trimethoprim: 300 mg twice daily (unlicensed use).
• During pregnancy and lactation:
• Erythromycin: 500 mg twice daily (not erythromycin estolate).
Although all tetracyclines appear to have comparable efficacy against
inflammatory acne lesions, lymecycline and doxycycline are preferred due
to their lack of interaction with milk and once-daily dosage. Due to the risk
of irreversible pigmentation and other adverse effects with minocycline, it
should not be used as a first-line therapy. Published trials show a trend towards
superior efficacy for tetracyclines compared with macrolides.Trimethoprim is
unlicensed for the treatment of acne, and therefore considered a third choice
antibiotic to be used under specialist recommendation.
Failure to respond may be a consequence of the following:
• Poor patient adherence.
• P. acnes resistance.
• Inadequate dose or duration of therapy.
• Interactions impairing antibiotic absorption.
++Baseline investigations & considerations
The emergence of antibiotic resistant strains of P. acnes has been clearly
documented since the 1990s. However, the clinical relevance of this is unclear
as it is not necessarily associated with therapeutic failure. The additional antiinflammatory actions of antibiotics may be of importance in their effectiveness
in acne.
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Acne antibiotics
Suspect resistance if:
• The patient has received many long-term sequential oral and/or topical
antibiotics.
• Nonresponding patient.
• The patient relapses after the initial response to treatment despite
continued therapy.
Prevent resistance by:
• Appropriate dosing.
• Avoid co-prescribing dissimilar oral and topical antibiotics.
• Avoid topical antibiotic monotherapy.
• Limit the use of systemic antibiotics (both indication and duration).
• Encourage excellent adherence.
Treat suspected resistance by:
• Use of therapies that are associated with a lower prevalence of resistance
(P. acnes resistance to tetracyclines is less prevalent than combined resistance
to clindamycin and erythromycin; and strains resistant to tetracycline and
doxycycline may not be resistant to minocycline).
• Use of non-antibiotic therapies, i.e. oral isotretinoin, hormonal therapy,
non-antibiotic topical therapy.
++Monitoring
• Routine monitoring is not required before or during treatment of acne with
oral antibiotics.
• Baseline investigations and monitoring every 3 months for hepatotoxicity
and lupus (ANA and LFTs) have been suggested for patients receiving
minocycline.
++Contraindications
• Tetracyclines (doxycycline, minocycline, tetracycline, lymecycline):
• Severe renal impairment (except doxycycline).
• Children <12 years.
• Pregnancy and lactation.
• Systemic lupus erythematosus or family history of lupus (minocycline).
• Erythromycin:
• QT interval prolongation, and combination with agents that can result in
QT interval prolongation (risk of ventricular arrhythmias).
• Hypokalaemia, hypomagnesaemia.
• Severe hepatic impairment, history of hepatitis caused by macrolides,
cholestasis.
• Trimethoprim:
• Severe renal impairment.
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Acne antibiotics
•
•
Haematological disease (thrombopenia, granulocytopenia, megaloblastic
anaemia),
Pregnancy and lactation.
++Cautions
• Tetracyclines:
• Hepatic impairment.
• Renal impairment (dose reduction, consider determining drug serum
level in long-term therapy – see Systemic Therapy & Kidney Disease).
• Personal or close family history of lupus-like disorders (minocycline).
• Myasthenia gravis, due to possible potentiation of neuromuscular
blockade.
• Erythromycin:
• Hepatic impairment.
• Severe renal impairment (risk of irreversible hearing loss).
• Trimethoprim:
• Hepatic impairment.
• Renal impairment (dose reduction required).
• Folic acid deficiency.
++Important drug interactions
Tetracyclines should not be prescribed with the following:
• Oral retinoids, due to a potential increased risk of benign intracranial
hypertension (see Isotretinoin).
• Penicillins, as the bactericidal action of penicillins may be reduced due to
pharmacodynamic antagonism.
Care should be taken if tetracyclines are prescribed with the following:
• Digoxin, due to increased absorption and potential toxicity of digoxin.
• Oral anticoagulants: tetracyclines may enhance anticoagulant effects due to
a reduction in prothrombin activity.
• Salts of calcium, iron, strontium, bismuth, aluminium, zinc, magnesium,
antacids and quinapril (contains magnesium) may reduce absorption of
tetracyclines and diminish their effectiveness.
• Oral contraceptive pills (OCP): there may be short-term impairment in the
contraceptive effects of oestrogen-containing pills due to alteration of gut
flora.
• Oral hypoglycaemic agents: the glucose lowering effect of sulphonylureas
may be increased.
• Ciclosporin (cyclosporine) and methotrexate, due to possible increased
toxicity.
• Diuretics (lymecycline).
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Acne antibiotics
Erythromycin has numerous drug interactions due to its inhibitory effects on
the cytochrome p450 (CYP450) 3A isoenzyme, and the cardiotoxicity of certain
drugs may also be increased. It should not be prescribed with the following:
• Antipsychotic drugs including droperidol, pimozide, sertindole.
• Cisapride (discontinued in the UK and USA), due to the risk of ventricular
arrhythmias.
• Ergot alkaloids (unlicensed use for headache), due to increased risk of
ergotism.
• Mizolastine, due to QT prolongation.
• Simvastatin, lovastatin, due to increased risk of myopathy.
Care should be taken if erythromycin is prescribed with the following:
• Atorvastatin and pravastatin: a lower dose should be used and patients
monitored carefully for signs of myopathy. Other statins which are not
metabolized by CYP3A4 (rosuvastatin, fluvastatin) may carry less risk of
myopathy.
• Ciclosporin metabolism may be inhibited, with increased toxicity (see
Ciclosporin).
• Colchicine, due to increased risk of toxicity (see Colchicine).
• Coumarin anticoagulants (e.g. warfarin), due to increased anticoagulant
effects.
• Digoxin plasma concentrations are raised with risk of toxicity.
• OCP: there may be a short-term impairment in the contraceptive effects of
oestrogen-containing pills due to alteration of gut flora.
• Anticonvulsants (phenytoin, carbamazepine clozapine and valproic acid),
due to decreased metabolic clearance and increased plasma levels.
• Theophylline, due to increased plasma theophylline, which may cause
nausea, vomiting and seizures.
• Verapamil, due to increased risk of cardiotoxicity.
Trimethoprim should not be prescribed with the following:
• Cytotoxics (methotrexate, mercaptopurine, azathioprine), due to the
increased risk of increased bone marrow toxicity.
Care should be taken if trimethoprim is prescribed with following:
• Ciclosporin, due to possible increased nephrotoxicity.
• Coumarin anticoagulants, due to possible enhanced anticoagulant effect.
• Dapsone: plasma concentrations of both drugs may increase.
• Pyrimethamine, due to possible blood dyscrasia.
• OCPs, due to possible impact on the contraceptive efficacy.
• Oral hypoglycaemic agents, due to possible enhanced effects.
• Phenytoin, lamivudine, zidovudin, digoxin, procainamide, due to increased
plasma level and potential toxicity.
Oral antibacterial drugs inactivate oral typhoid vaccine and should be avoided
3 days before and after administration.
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Acne antibiotics
++Adverse effects & their management
Nonspecific effects of oral antibiotic therapy include the following:
• Gastrointestinal: nausea, colic and diarrhoea may occur with all acne
antibiotics but are particularly common with erythromycin as it enhances
gastroduodenal motility. Symptoms may respond to dividing dosage or
occasional use of co-phenotrope (Lomotil®, a mixture of 2.5 mg diphenoxylate
hydrochloride and 25 µg atropine sulfate). Treatment with pro-biotic agents
(such as Pro-Symbioflor®, a suspension containing Escherichia coli and
E. faecalis), can help to regulate the intestinal flora. Epigastric discomfort is
common with doxycycline and may be improved by taking the medication
after food (which may decrease absorption up to 20%).
• Vaginal candidiasis is a common side-effect. Effective therapy is available
without prescription.
• Generalized drug eruption and fixed drug eruptions are uncommon,
although 4% of patients may develop a widespread maculopapular rash
with trimethoprim. Stevens–Johnson syndrome, (an immune complexmediated syndrome involving the skin and mucous membranes, which
should be managed in an intensive care unit) and toxic epidermal necrolysis
are rare (<0.1%) adverse effects of acne antibiotics.
• Hormonal contraceptive failure: broad-spectrum antibiotics have been
associated with impaired effectiveness of the combined OCP, due to alteration
in large bowel flora and reduced enterohepatic circulation of oestrogen.
Although the magnitude of this effect appears modest, additional nonhormonal methods of contraception should be used during the first month
of antibiotic therapy. If a woman on long-term acne antibiotic therapy
(>3 weeks) commences a combined OCP, additional precautions are not
needed. The American College of Obstetricians and Gynecologists advises
that tetracycline, doxycycline, ampicillin and metronidazole do not affect
oral contraceptive steroid levels.
• Clostridium difficile-associated diarrhoea (CDAD) and especially
pseudomembranous colitis is very rare with oral acne antibiotics. It requires
prompt and specific treatment with metronidazole or vancomycin.
Specific drug side-effects include the following:
• Hyperpigmentation with minocycline: this may affect various body sites
including skin, nails, mucosae, eyes and bones (‘black bones’) and is due
to deposition of black metabolites of the drug. Blue/grey/muddy brown
discolouration may be localized or diffuse. The risk is generally related to the
duration of treatment, and pigmentation may persist after stopping therapy,
especially on sun exposed sites. Q-switched ruby laser therapy may help.
• Photosensitivity (phototoxicity) may occur with all tetracyclines, but
is especially common with doxycycline and demeclocycline and most
rare with minocycline. Phototoxicity appears clinically as exaggerated
sunburn, sometimes with oedema and blistering, and may be accompanied
by onycholysis.
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• Benign intracranial hypertension is a rare adverse effect of tetracyclines,
especially with doxycycline. It usually occurs within 4 weeks of starting
therapy. Symptoms include headache, transient visual disturbances, diplopia,
pulsatile tinnitus, nausea and vomiting. It may result in permanent loss of
visual fields. If suspected an ophthalmological or neurological examination
for papilloedema is required.
• Minocycline-associated drug hypersensitivity syndrome ia a rare and
potentially fatal drug reaction. It occurs within the first 1–2 months of
treatment and presents with a generalized rash, lymphadenopathy and
fever.
• Minocycline induced lupus-like syndrome with hepatitis, polyarthralgia,
and positive antinuclear antibodies has been reported rarely (approximately
1 case per 10,000 person-years) especially with prolonged treatment.
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) may also occur
in some individuals. The risk of developing a lupus-like disorder has been
estimated to be increased 2–5-fold during minocycline treatment, so the use
of this drug should be carefully evaluated.
• Oesophagitis may occur with all tetracyclines, especially doxycycline.
Medication should be taken when upright and with plenty of water
to reduce the risk. Symptoms usually settle within a few days of drug
withdrawal.
• Tooth staining is a recognized adverse effect of all tetracyclines. This may
affect the primary or secondary dentition and has been reported to develop
in adults after prolonged therapy. It occurs due to the ability of this group
of antibiotics to chelate calcium ions, leading to their incorporation into
teeth, cartilage and bone.
• Drug induced liver injury is a very rare adverse effect of tetracyclines (see
Systemic Therapy & Liver Disease). Cholestatic hepatitis has been reported
as a hypersensitivity reaction to the estolate salt of erythromycin. Symptoms
include fever and abdominal pain, with eosinophilia and abnormal LFTs.
• Idiosyncratic blood dyscrasias including agranulocytosis, thrombocytopenia
and anaemia may occur with trimethoprim.
++Use in special situations
Pregnancy & pre-conception
Tetracyclines (FDA Category D) are contraindicated. They cross the placenta and
can have toxic effects on fetal development, particularly retardation of skeletal
development. Embryotoxicity in early pregnancy has been noted in animals.
Use of tetracyclines during the last half of pregnancy may cause permanent
discolouration of the infant’s teeth.
Erythromycin (FDA Category B) may be considered as a suitable oral therapy
in severe disease in pregnancy. The estolate salt is contraindicated.
Trimethoprim (FDA Category C) should be avoided in pregnancy, as it is a
folate antagonist.
Negative effects on male fertility have been reported with tetracyclines and
erythromycin.
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Acne antibiotics
Lactation
Tetracyclines should not be used as they are excreted in breast milk and
may cause permanent tooth discolouration and enamel hypoplasia in the
developing infant.
Erythromycin is excreted in breast milk, but can be considered in severe cases
(strict indication).
Trimethoprim: due to relatively low rate of excretion in breast milk,
trimethoprim can be considered in severe cases (strict indication).
Children
Tetracyclines are contraindicated in young children due to the risk of permanent
tooth discolouration. The British National Formulary advises against their
use under the age of 12 years due to the risk of permanent dental staining.
Organizations in the USA recommend a lower age limit of under 9 years.
Erythromycin is licensed for use in childhood and may be considered in
severe infantile acne.
++Essential patient information
Females taking the combined OCP should be warned about the need for
increased contraceptive precautions for the first month of oral antibiotic
therapy. Patients should be advised about the expectable outcome of therapy
(e.g. slow onset of effect) and about the need for excellent adherence to
maximize effectiveness. They should also be informed of the specific drug sideeffects.
With acknowledgements to W. Cunliffe, author of this chapter in the 1st
edition
++Further reading
Garner SE, Eady A, Bennett C, Newton JN, Thomas K, Propescu CM.
Minocycline for acne vulgaris – efficacy and safety. Cochrane Database Syst Rev
2012;8:CD002086.
Ingram JR, Grindlay DJC, Williams HC. Management of acne vulgaris: an
evidence-based update. Clin Exp Dermatol 2010;35:351–4.
Margolis DJ, Hoffstad O, Bilker W. Association or lack of association between
tetracycline class antibiotics used for acne vulgaris and lupus erythematosus.
Br J Dermatol 2007;157:540–6.
Millsop JW, Heller MM, Eliason MK, Murase JE. Dermatological medication
effects on male fertility. Dermatol Ther 2013;26:337–46.
Nast A, Dréno B, Bettoli V, et al. European Evidence-based (S3) Guidelines for
the treatment of acne. J Eur Acad Dermatol Venereol 2012;26(Suppl. 1):1–29.
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Alitretinoin
Anand Patel & John English
++Classification & mode of action
Alitretinoin (9-cis-retinoic acid) is an endogenously occurring retinoid which is
structurally related to vitamin A. It acts as a pan-agonist at retinoid receptors,
binding with high affinity to both retinoic acid receptors (RARs) and retinoid
X receptors (RXR). The latter are capable of binding to a range of different
nuclear receptors to modulate gene expression (Figure 1). The precise mode of
action of alitretinoin in chronic hand eczema remains unclear, but retinoids are
known to affect multiple processes at a cellular level including proliferation,
differentiation and apoptosis. They may also have anti-inflammatory and
immunomodulatory effects, including suppression of nitric oxide and tumour
necrosis factor (TNF)-alpha production, impairment of T-cell activation and
down-regulation of chemokine synthesis (CXCL9 and CXCL10), thereby
impairing the recruitment of inflammatory leukocytes. Alitretinoin has been
shown to suppress the expression of co-stimulatory molecules on the surface
of antigen-presenting cells, which may be of relevance to a therapeutic effect
in contact dermatitis. In contrast to isotretinoin, alitretinoin only has a minimal
effect on sebum secretion.
Alitretinoin has a much shorter half-life than acitretin and isotretinoin,
and levels of the drug and its metabolites return to the normal range within
2–7 days of stopping established treatment.
9cRA
RAR
RXR
DNA Retinoid response element
Target gene
Proliferation, differentiation
and apoptosis
FIGURE 1 Schematic diagram of the retinoic acid receptor (RAR), retinoid X receptor
(RXR) and binding to the retinoid response element in the promotor region of a
gene.
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Alitretinoin
++Indications & dermatological uses
• The only licensed indication for alitretinoin in the UK is severe chronic hand
eczema that is unresponsive to potent topical steroids in adults. Severe
chronic hand eczema is defined by a clinical score – the Physician’s Global
Assessment (PGA) – and a Dermatology Life Quality Index (DLQI) score of
at least 15.
A large randomized placebo controlled study has demonstrated the efficacy
of alitretinoin in adult patients with severe chronic hand eczema (referred to
as the ‘BACH’ – Benefit of Alitretinoin in Chronic Hand eczema study). This
reported that almost half of all patients receiving the higher (30 mg daily)
dose achieved a rating of ‘clear’ or ‘almost clear’ at the 24 week endpoint. The
lower dose (10 mg daily) was less effective but superior to placebo.
Both hyperkeratotic disease and pompholyx/fingertip variants of hand eczema
were reported to respond.
Smaller studies have reported benefit in palmoplantar psoriasis, chronic
hyperkeratotic palmar psoriasis and chronic foot eczema. Isolated reports are
emerging of its benefit in Darier’s disease, Hailey–Hailey disease, pityriasis
rubra pilaris and mycosis fungoides.
++Formulations/Presentation
• 10 mg and 30 mg alitretinoin in soft capsules (Toctino®).
• Capsules contain soya bean oil and sorbitol.
A topical formulation of alitretinoin is FDA approved in the USA for
use in acquired immunodeficiency syndrome (AIDS) associated Kaposi’s
sarcoma.
Special point
Alitretinoin and acitretin are both prescribed by dermatologists and are ‘sound
alike’ drugs. This raises the potential for prescribing and dispensing error with
potentially serious consequences and litigation. Prescribing by brand may
reduce this risk. Pharmacists who dispense alitretinoin should be alert to the
potential for confusion.
++Dosages & suggested regimens
The usual starting dose is 30 mg once daily. The capsule should be swallowed
whole with/after a meal to maximize bioavailability. If side-effects are not
tolerated, dosage can be reduced to 10 mg daily. In patients with diabetes,
hyperlipidaemia or risk factors for cardiovascular disease, a lower starting dose
of 10 mg once daily is recommended. This can be increased if necessary to a
maximum daily dose of 30 mg.
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Alitretinoin
The onset of action is slow, but there is usually some improvement within
the first month. UK guidelines recommend that clinical response should be
assessed at 12 weeks, and treatment discontinued if inadequate. For those who
respond, the total duration of treatment is recommended to be 12–24 weeks.
It has been reported that some patients who have not responded by these time
intervals may nevertheless benefit from more prolonged therapy. Treatment
should be stopped once an adequate clinical response (clear or almost clear)
has been achieved. Relapse tends to occur slowly over several months and
subsequent retreatment may be necessary.
++Contraindications & cautions
The following are contraindications to systemic retinoid therapy including
alitretinoin:
• Pregnancy (see below).
• Hypersensitivity to retinoids or excipients.
Alitretinoin capsules (Toctino®) contain soya bean oil. While soya beans
and peanuts are both legumes, each of these foods stand alone in terms of
immunogenicity and patients who are peanut allergic do not routinely need
to avoid soya-containing products. In cases where the history is unclear,
immediate type allergy testing can be undertaken (skin prick tests or specific
immunoglobulin [Ig]E measurement) and if negative, a test dose given under
clinical supervision.
Blood donation: should be avoided during treatment and for at least
1 month after stopping treatment.
Extra caution should be taken when alitretinoin is prescribed in the following:
• Liver dysfunction/cirrhosis (close monitoring is required; see Systemic
Therapy & Liver Disease).
• Renal impairment (alitretinoin metabolites are mainly excreted in the urine;
see Systemic Therapy & Kidney Disease).
• Uncontrolled hypothyroidism.
• Uncontrolled hyperlipidaemia.
• Diabetes.
• Depression.
• Disorders associated with ocular dryness.
++Important drug interactions
• Ketoconazole: is a strong inhibitor of cytochrome P450 (CYP450) 3A4
metabolism of alitretinoin that impairs and increases alitretinoin plasma
concentrations .
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• Simvastatin: a slight reduction of simvastatin plasma levels was observed
when co-administered with alitretinoin.
• Vitamin A: supplements are contraindicated due to the risk of
hypervitaminosis/retinoid toxicity.
• Tetracyclines: due to the increased risk of benign intracranial hypertension.
++Baseline investigations & considerations
Patch testing should be performed prior to commencing alitretinoin to exclude
a significant underlying contact allergy. This is an important consideration as
allergic contact dermatitis of the hands may be impossible to distinguish from
an endogenous dermatitis on clinical grounds alone.
Patients with diabetes, history of hyperlipidaemia, or risk factors for
cardiovascular disease should be identified and screened prior to commencing
treatment and closely monitored during treatment. Baseline investigations
consist of:
• Pregnancy testing (Pregnancy Prevention Programme, PPP).
• BP.
• FBC (CBC).
• Urea, electrolytes and creatinine.
• LFTs.
• Fasting lipids & glucose.
• Thyroid function tests (if clinically indicated).
++Monitoring
• The PPP must be followed in females of reproductive age. (See below and
Isotretinoin.)
• Fasting lipids (cholesterol and triglycerides) should be monitored in order
to detect hyperlipidaemia. In the absence of specific advice from the
manufacturers, testing every 3 months is reasonable. Monthly monitoring
may be indicated for those with diabetes, pre-existing hyperlipidaemia or
risk factors for cardiovascular disease.
• Urea and electrolytes and LFTs monitoring may be sensible though not
specifically advised by the manufacturer.
• Thyroid function should be monitored in those with pre-existing disease. In
normal individuals low thyroid stimulating hormone (TSH) levels may occur
during treatment but thyroid medication is not usually required.
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Alitretinoin
++Adverse effects & their management
• Teratogenicity: in females of childbearing age the PPP must be followed
unless the individual has signed a disclaimer that she is not sexually active
and at risk of pregnancy. The monitoring requirements are identical with
those for oral isotretinoin (see Isotretinoin). In the UK this includes the
following:
• Pregnancy testing prior to commencing alitretinoin, at monthly
intervals thereafter during treatment and at 5 weeks after completion
of treatment.
• Females at risk of pregnancy must use adequate contraception for at
least 1 month before starting treatment, during treatment and for at
least 1 month after stopping treatment.
• Females should be advised to use at least one method of highly
effective contraception and ideally they should use two methods.
The progesterone-only oral contraceptive pill (OCP) (mini-pill) or
barrier contraception alone are not considered adequate but can be
combined with other contraceptive methods. Effectiveness of hormonal
contraceptives is not impaired by alitretinoin.
• Females should be advised to discontinue treatment and to seek prompt
medical attention if they become pregnant during treatment or within
1 month of stopping treatment.
• Hyperlipidaemia: raised total cholesterol and triglycerides may occur during
treatment. This effect is usually dose related and reversible and usually
responds to dosage reduction. If these measures fail and hyperlipidaemia is
severe, treatment must be discontinued. Hypertriglyceridaemia is associated
with an increased risk of pancreatitis, especially if levels exceed 9 mmol/L.
• Headache and flushing are the commonest initial adverse effects, and
affect about half of all patients. They are a more frequent problem with
alitretinoin than other systemic retinoids and tend to improve after several
weeks of continued treatment. Simple analgesics and taking the medication
shortly before sleep may be helpful.
• Pseudotumour cerebri (PTC)/benign intracranial hypertension is a very
rare adverse effect common to all retinoids, especially when taken with
tetracyclines. Symptoms are severe headache, nausea and vomiting and
visual disturbance. If untreated, there is a risk of permanent visual loss.
• Ocular adverse effects include blurred vision, conjunctivitis, photosensitivity,
impaired night vision, cataracts, keratitis and eye irritation.
• Cutaneous adverse effects include flushing and pruritus, dryness, cheilitis,
epistaxis asteatotic eczema, vasculitis and alopecia. Cheilitis and alopecia
are less common than with isotretinoin and acitretin respectively.
Photosensitivity can occur during treatment with alitretinoin so patients
should be advised to avoid use of sun beds and protect their skin against
excessive sun exposure.
• Musculoskeletal adverse effects common to oral retinoids include exercise
induced fatigue, myalgia and arthralgia. These may be associated with
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elevation of serum creatine kinase. Radiological changes with long-term
retinoid therapy include hyperostosis and spondylitis (rare).
• Psychiatric disturbance including depression is a potential adverse effect of
all oral retinoids, especially isotretinoin (see Isotretinoin). It is not yet clear
if this applies to alitretinoin which has generally been used in older patients
with a different psychosocial profile from those with acne. If patents are
affected by mood change, the PHQ-9 can be used as a simple screening tool
for depression (see Appendix 1).
++Use in special situations
Pregnancy & pre-conception
Alitretinoin is a teratogen and absolutely contraindicated in pregnancy. Females
should not become pregnant within 1 month of discontinuing treatment (see
Isotretinoin PPP).
Very low amounts of alitretinoin have been detected in the semen of males
taking alitretinoin. As with the other oral retinoids, isotretinoin and acitretin,
these levels are too low to pose a teratogenic risk to the unborn baby of a
female partner.
Topical alitretinoin is FDA Category D.
Lactation
Alitretinoin is lipophilic and likely to be distributed to breast milk so it is
contraindicated in breastfeeding females.
Children
Alitretinoin is only licensed for use in those over 18 years. Clinical trials of high
dose 9-cis-retinoic acid in childhood malignancy reported PTC as a frequent
adverse effect, especially in younger children. There is insufficient evidence at
present to support use of alitretinoin in dermatological disease in children.
++Essential patient information
• Patients should be informed of the reasons for treatment, the likely sideeffects and the monitoring requirements.
• It should be explained that treatment will cease if there is an inadequate
response at 3 months, after completion of a 6 months’ course or earlier if
disease remission is achieved.
• Females should be fully informed of the requirements of the PPP.
With acknowledgements to Raja Sivamani, Jillian Millsop and Vivian Shi who
reviewed this chapter from an international perspective.
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Alitretinoin
++Further reading
Brown RG (ed). Pharmacology of oral alitretinoin: a novel treatment for severe
chronic hand eczema. Clin Exp Dermatol 2011:36(Suppl. 2):1–34.
English J, Aldridge R, Gawkroger DJ, et al. Consensus statement on the
management of chronic hand eczema. Clin Exp Dermatol 2009;34(7):761–9.
Garnock-Jones KP, Perry CM. Alitretinoin in severe chronic hand eczema. Drugs
2009:69:1625–34.
Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication
effects on male fertility. Dermatol Therapy 2013;26:337–46.
(NICE) NIoHaCE Final appraisal determination – Alitretinoin for severe chronic
hand eczema URL http://www.nice.org.uk/nicemedia/pdf/TA177Guidance.pdf.
Patel AN, Wooton CI, Babakinjad P, English JS. Alitretinoin: the Nottingham
experience. Clin Exp Dermatol 2014;39:224–5.
Paulden M, Rodgers M, Griffin S, et al. Alitretinoin for the treatment of severe
chronic hand eczema. Health Technol Assess 2010;14(Suppl. 1):39–46.
Ruzicka T, Lynde CW, Jemec GBE, et al. Efficacy and safety of oral alitretinoin
(9-cis-retinoic acid) in patients with severe chronic hand eczema refractory
to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. B J Dermatol 2008;158:808–17.
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Androgens
Shirin Zaheri & Iaisha Ali
++Classification & mode of action
Androgens belong to class C-19 steroids produced primarily by the testes,
adrenal cortex (the major source in females) and ovaries. Testosterone and its
more potent 5α-reduced derivative, 5α-dihydrotestosterone (DHT), are the two
predominant physiological androgens. The ovaries produce oestradiol. Steroids
with oestradiol-like function are called oestrogens. Testosterone and oestradiol
circulate in plasma bound to plasma proteins, mainly sex hormone binding
globulin (SHBG). The hepatic synthesis of SHBG is stimulated by oestrogens and
inhibited by testosterone.
Anabolic steroids are sex hormones with some androgenic activity (increased
skeletal muscle mass, increased organic mass of bone and retention of nitrogen).
They cause less virilization than androgens in females and are helpful in some
dermatological conditions. The actions of anabolic steroids are similar to male
sex hormones, with the possibility of causing serious disturbances of growth
and sexual development if given to children.
Danazol is a synthetic steroid derived from ethisterone. It is a weak androgen
with additional antiprogestogenic and antioestrogenic actions and interferes
with gonadal steroid synthesis. It also affects pituitary gonadotrophins, with
inhibition of the mid-cycle surge of follicle stimulating hormone (FSH) and
luteinizing hormone (LH), as well as altering the pulsatility of LH, and can
reduce the mean plasma levels of these gonadotrophins after the menopause.
Danazol has a wide range of actions on plasma proteins, including increasing
prothrombin, plasminogen, antithrombin III, alpha-2 macroglobulin, C1 esterase
inhibitor, and erythropoietin and reducing fibrinogen, thyroid binding and
SHBG. It increases the proportion and concentration of testosterone carried
unbound in plasma. In addition, danazol corrects partially or completely the
primary biochemical abnormality of hereditary angioedema by increasing
the levels of the deficient C1 esterase inhibitor. As a result of this action, the
serum levels of the C1 esterase inhibitor and C4 component of the complement
system are increased.
The suppressive effects of danazol on the hypothalmic–pituitary–gonadal
axis are reversible, cyclical activity reappearing normally within 60–90 days
after therapy.
Stanozolol is a synthetic derivative of testosterone and has more powerful
androgenic effects, hence its use as a performance enhancing drug by
bodybuilders. It is no longer licensed for use in the UK, but remains approved
by the USA FDA. It suppresses the gonadotrophic functions of the pituitary and
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Androgens
may exert a direct effect upon the testes. It can increase collagen production
and decrease the antianabolic action of cortisone. It is also reported to increase
fibrinolysis. It corrects the formation of kinin or kinin-like factors, which may
be associated with oedema and swelling seen in hereditary angioedema.
++Indications & dermatological uses
• Danazol is licensed for the treatment of endometriosis and benign fibrocystic
breast disease. Stanozolol is no longer licensed for use in the UK.
• Danazol has been used in the long-term management of hereditary
angioedema in patients who have frequent and/or severe episodes. It has
also been used for recalcitrant cholinergic urticaria and lividoid vasculopathy.
• Stanozolol has been used for hereditary angioedema and a range
of
dermatological
diseases
including
hereditary
angioedema,
vascular manifestations of Behçet’s disease, cryofibrinogenaemia and
lipodermatosclerosis.
The usage of these drugs for hereditary angioedema prophylaxis may decrease
as on-demand self-administered therapy with C1 inhibitor concentrate and
bradykinin analogues becomes more widespread.
++Dosages & suggested regimens
• Danazol: 50 mg, 100 mg and 200 mg capsules.
• Stanozolol: 2 mg tablets, scored 5 mg tablets.
Danazol: for hereditary angioedema the initial dose is 200 mg 2–3 times per
day, with dose reductions of 50% at intervals of at least 1–3 months. If an attack
occurs, dosage is increased by increments up to 200 mg/d. Treatment is usually
given continuously and dosage should be kept at the lowest effective level.
Short-term treatment may also be given before elective surgical interventions.
In recalcitrant cholinergic urticaria the usual daily dosage of danazol is 600mg.
Doses of up to 800 mg per day are used for endometriosis.
In fertile females, treatment should be started during menstruation,
preferably on the first day of the cycle and adequate non-hormonal
contraception used (see Use in special situations).
Stanozolol: for hereditary angioedema, initial doses range from 2.5 to 10
mg daily according to severity, with maintenance doses of 2 mg daily or on
alternate days or 2.5 mg three times weekly.
For vascular manifestations of Behçet’s disease the usual dose is 10 mg daily.
++Baseline investigations & considerations
• FBC (CBC)/LFTs/fasting lipids/glucose.
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Androgens
• Pregnancy test and contraception for females of childbearing potential (see
above and Use in special situations).
++Monitoring
Hepatotoxicity and liver tumours have been reported in rare instances, so the
lowest doses should be used with careful monitoring as below:
• FBC.
• LFTs.
• Fasting lipids.
• Fasting glucose.
• Biannual hepatic ultrasonography.
• Clinical assessment of females for features of virilization.
Interactions with laboratory function tests: danazol may interfere with
laboratory determination of testosterone or plasma proteins; stanozolol may
interfere with thyroid function tests.
++Contraindications
Both drugs are contraindicated in the following:
• Pregnancy and lactation.
• Androgen sensitive tumours (e.g. prostate cancer).
• Severe impairment of hepatic, renal or cardiac function.
• Thromboembolic disease – active or past history of events.
• Acute porphyria.
• Hypersensitivity to the active drug or excipients.
• Undiagnosed/abnormal vaginal bleeding.
Stanozolol is not recommended for use in pre-menopausal females, those with
insulin dependent diabetes and hypercalcaemia/hypercalciuria.
++Cautions
• Underlying medical disease associated with fluid retention: cardiac, renal
and hepatic disorders, migraine, epilepsy, polycythaemia, lipoprotein
disorder, diabetes.
• The elderly.
• Patients who have shown marked or persistent androgenic response to
previous gonadal steroid therapy.
• Malignant disease – before treatment initiation, the presence of hormone
dependent carcinoma should be excluded at least by careful history and
clinical examination. The risk of ovarian cancer may be increased.
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Androgens
++Important drug interactions
• Anticonvulsant therapy: use of androgens may increase plasma levels of
carbamazepine, phenobarbital and phenytoin.
• Antidiabetic therapy: requirements may increase as androgens increase
insulin resistance and impair glucose tolerance.
• Antihypertensive therapy: requirements may increase due to hypertensive
actions of synthetic androgens.
• Oral anticoagulant therapy may be potentiated.
• Gonadal steroid therapy may be affected by danazol.
• Migraine therapy: danazol may provoke migraine and possibly reduce the
effectiveness of medication to prevent that condition.
• Alpha calcidol: danazol may increase the calcaemic response in primary
hypoparathyroidism, necessitating a reduction in dosage of this agent.
• Ciclosporin (cyclosporine) and tacrolimus: danazol can increase the plasma
level of ciclosporin and tacrolimus, leading to increased renal toxicity.
• Levothyroxine activity may be enhanced by stanozolol.
• Statins: the risk of myopathy and rhabdomyolysis is increased by concomitant
administration of danazol with statins such as simvastatin, atorvastatin and
lovastatin.
++Adverse effects & their management
• Androgenic: mild effects are common and include acne, weight gain,
increased appetite and seborrhoea. Menstrual irregularities, vaginal dryness,
flushing, changes in libido and a reduction in breast size may also occur.
Treatment should be discontinued if signs of virilization develop (hirsutism,
pattern hair loss, voice change). If treatment is discontinued promptly, these
effects are usually reversible. However, permanent clitoral hypertrophy has
occurred with continued therapy. Male fertility and sexual function may be
affected (see Use in special situations).
• Hepatic: prolonged therapy with large doses increases the risk of hepatic
neoplasms and hepatocellular carcinomas. Isolated increases in serum
transaminase levels, cholestatic jaundice and benign hepatic adenomata
may also occur, so careful monitoring is indicated. Peliosis hepatis has been
reported (a condition in which hepatic and sometimes splenic tissue is
replaced with blood-filled cysts).
• Renal: haematuria has been reported with prolonged use in patients with
hereditary angioedema.
• Metabolic and pro-atherogenic adverse effects include increased insulin
resistance and impaired glucose tolerance with raised plasma glucagon.
Increase in low-density lipoprotein (LDL) cholesterol and decrease in
high-density lipoprotein (HDL) cholesterol may occur. Routine laboratory
monitoring is therefore indicated.
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Androgens
• Haematological abnormalities include increased erythropoiesis and
polycythaemia, leukopenia, thrombocytopenia, eosinophilia and alteration
in clotting factors with prolongation of the prothrombin time (PT).
• Central nervous system adverse effects include dizziness, headache, fatigue,
insomnia and mood disturbance (anxiety, depression, aggression). Benign
intracranial hypertension has been reported (symptoms include severe
headache, nausea and visual disturbance). Aggravation of epilepsy and
carpal tunnel syndrome may occur.
• Ophthalmological adverse effects include blurred vision and altered
refraction, which may affect those who wear contact lenses or spectacles.
• Gastrointestinal adverse effects include nausea, vomiting, dyspepsia and
pancreatitis.
• Pulmonary: pleuritic pain, interstitial pneumonitis.
• Cardiac: hypertension may be the most significant long-term effect of
therapy. Combined with the deleterious alterations in metabolic profile (see
above) this may increase cardiovascular risk. Other cardiac effects include
palpitations and tachycardia. Thrombotic events include sagittal sinus,
cerebrovascular thrombosis and myocardial infarction.
• Cutaneous adverse effects include rash and pruritus, photosensitivity,
altered skin pigmentation, exfoliative dermatitis and erythema multiforme.
Immediate type hypersensitivity has been reported.
• Musculoskeletal and connective tissue adverse effects include muscle
cramps and tremors, fasciculation, limb pain, joint pain and joint swelling.
Premature epiphyseal closure may occur in children and adolescents.
• Alcohol: subjective intolerance in the form of nausea and shortness of
breath has been reported with danazol.
++Use in special situations
Pregnancy & pre-conception (FDA Category X)
Androgens are contraindicated in pregnancy as they are may cause virilization
of the female fetus. In males, use of synthetic androgens may be associated
with reduced spermatogenesis as they inhibit FHS production. Other effects
include altered libido and priapism.
Lactation
Androgens are contraindicated as it is not known whether they are excreted
in human milk.
Children
The use of synthetic androgens is not recommended in pre-pubertal children.
Risks include precocious sexual development in boys, virilization in girls and
premature closure of the epiphyses in both sexes. If used in children, growth
should be carefully monitored with radiography if indicated to assess bone
age.
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Androgens
++Essential patient information
• These drugs should not be taken during pregnancy as they may be harmful
to an unborn baby.
• Alcohol should be avoided as it may cause sickness or shortness of breath.
• Patients should be advised to stop taking this medicine and consult
their doctor if they experience any of the following symptoms: hair loss
(especially male baldness); marked increase in facial or body hair; voice
change – hoarseness or pitch change; enlargement of the clitoris; altered
vision; severe headache and vomiting; stabbing pains and/or unusual
swelling in one leg; pain on breathing or coughing; coughing up blood;
sudden breathlessness; sudden severe chest pain; or any other severe
unexplained symptom.
• Blood tests to monitor liver function are required while taking this medicine.
Symptoms that may suggest a liver problem include persistent nausea and
vomiting, abdominal pain, or the development of jaundice.
With acknowledgements to Ekaterina P. Burova, author of this chapter in
the 1st edition, and William H. Eaglstein who reviewed this chapter from an
international perspective.
++Further reading
Bork K. Current management options for hereditary angioedema. Curr Asthma
Allergy Rep 2012;12:273–80.
Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary
angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol
2008;100(2):153.
Grattan CE, Humphreys F. Guidelines for evaluation and management of
urticaria in adults and children. Br J Dermatol 2007;157(6):1116–23.
Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safety of long-term
stanozolol therapy. J Allergy Clin Immunol 2007 Sep;120(3):654–8.
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Antiandrogens
Shirin Zaheri & Iaisha Ali
++Classification & mode of action
Antiandrogens are a group of drugs that block the action of androgens by two
broad mechanisms:
• Competitive inhibition of binding of androgens (testosterone and
dihydrotestosterone [DHT]) to the androgen receptor (androgen receptor
antagonists).
• Inhibition of the enzyme 5a-reductase that converts testosterone to DHT.
Androgen receptor antagonists include drugs, such as the steroidal
antiandrogens, spironolactone and cyproterone acetate, which also have
direct inhibitory effects on androgen synthesis, and the non-steroidal or ‘pure’
antiandrogens, flutamide and bicalutamide.
Flutamide is a potent antiandrogen. Its mechanism of action is inhibiting
androgen uptake and inhibiting nuclear binding of androgen in target tissues.
Bicalutamide is a newer and potent antiandrogen with similar mechanism of
action. These drugs were developed for the treatment of prostate cancer but
at lower doses have been found to be effective in the treatment of females
with hirsutism.
Spironolactone is an aldosterone antagonist and acts as a potassium
sparing diuretic. It inhibits the action of aldosterone on the distal renal tubule,
increasing sodium and water excretion and reducing potassium excretion.
Spironolactone is also a potent antagonist of the androgen receptor as well as
an inhibitor of androgen production, hence its use to treat androgen related
skin disease in females, namely hirsutism, androgenic alopecia and acne.
Drospirenone is a spironolactone analogue with antimineralocorticoid
activity. It also counteracts the oestrogen stimulated activity of the renin–
angiotensin–aldosterone system, and has also been shown to possess mild
antiandrogen activity. It is used in combination with an oestrogen for hormonal
oral contraception and hormone replacement therapy.
Cyproterone acetate is a synthetic derivative of 17-hydroxyprogesterone,
and acts primarily as an androgen receptor antagonist. It also has weak
progesterone agonist and glucocorticoid actions and inhibits androgen
synthesis. Cyproterone acetate was the first antiandrogen in clinical use and
was introduced 1964. A low dose combined preparation containing 2 mg
of cyproterone acetate and 50 µg of ethinyloestradiol was first marketed in
the UK in 1977, and subsequently reformulated with a lower oestrogen dose
(Dianette®) to reduce oestrogen related side-effects (oedema, melasma and
nausea).
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Antiandrogens
5-a-reductase inhibitors specifically prevent the conversion of testosterone
to its more potent metabolite DHT. In males with male pattern hair loss, the
balding scalp contains miniaturized hair follicles and increased amounts of DHT.
Administration of 5a-reductase inhibitors decreases scalp DHT concentrations
and inhibits the process responsible for miniaturization of scalp follicles. Males
with a genetic deficiency of type 2 5a-reductase do not suffer from male
pattern hair loss. The enzyme 5a-reductase exists as two isoenzymes; type 1 is
the dominant form in non-genital skin including the scalp and the sebaceous
glands, while type 2 is the dominant form in genital skin, the prostate and hair
follicles of the scalp, where miniaturization takes place. Finasteride selectively
inhibits the type 2 isoenzyme whereas dutasteride inhibits both type 1 and
type 2 5a-reductase. Although dutasteride reduces serum DHT levels more than
finasteride, both drugs have similar efficacy in the treatment of symptomatic
benign prostatic hyperplasia where they reduce prostate volume and have
similar adverse event profiles.
Other drugs with antiandrogenic effects include the corticosteroids,
prednisolone and dexamethasone, which inhibit adrenal androgen secretion,
particularly when given as a nocturnal dose (see Corticosteroids). Metformin,
an insulin sensitizing agent, has been suggested to have direct antiandrogen
actions on ovarian steroid synthesis as well as improving insulin sensitivity
and reducing insulin levels, which leads to a reduction in circulating free
androgens. Cimetidine has weak antiandrogenic effects due to competitive
inhibition of DHT at peripheral androgen receptors. Gonadotrophin releasing
hormone (GnRH) agonists inhibit pituitary gonadotrophin release and are the
most effective inhibitors of testosterone, while oral contraceptive pills (OCP)
inhibit ovarian androgen secretion. These agents have been reported to be
useful in the treatment of skin conditions.
++Indications & dermatological uses
Dermatological uses include the following (licensed indication *):
• Finasteride: androgenetic alopecia (in males*).
• Dutasteride: androgenetic alopecia.
• Flutamide: hirsutism, female pattern hair loss.
• Bicalutamide: hirsutism.
• Spironolactone: female pattern hair loss, acne and hirsutism.
• Drospirenone: acne.
• Cyproterone acetate as co-cyprindiol (Dianette®): acne (recalcitrant/severe*)
and/or hirsutism (moderate*) in females. The combined preparation also
functions as a hormonal contraceptive, but is not licensed specifically for
this purpose. It is not available in the USA.
• Cyproterone acetate (high dose): female hair loss and hirsutism.
Other licensed uses are:
• Finasteride, dutasteride: benign prostatic hyperplasia.
• Flutamide, bicalutamide: metastatic prostate cancer.
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Antiandrogens
• Spironolactone: oedematous conditions including congestive heart failure,
nephrotic syndrome, cirrhosis with ascites, malignant ascites and primary
aldosteronism.
• Drospirenone: OCP.
• Cyproterone acetate (high dose): male hypersexuality, advanced prostate
cancer.
++Formulations/Presentation
• Finasteride: 1 mg and 5 mg tablets. The 1 mg dosage is indicated for males
with androgenetic alopecia.
• Dutasteride: 0.5 mg soft capsules.
• Flutamide: 125 mg tablets.
• Bicalutamide: 25 mg tablets.
• Spironolactone: tablets containing 25 mg, 50 mg and 100 mg of
spironolactone. Oral suspension ranging from 5 to 100 mg/5 mL is available
on special order.
• Drospirenone: combined preparation of 3 mg drospirenone and 30
µg ethinyloestradiol as oral contraception (Yasmin®) and 0.5 mg of
drospirenone and 1 mg of estradiol (Angeliq®) as hormone replacement
therapy in post-menopausal females.
• Cyproterone acetate: scored tablets containing 50 mg and 100 mg
of cyproterone acetate. A combined preparation, co-cyprindiol, containing
cyproterone acetate 2 mg and ethinyloestradiol 35 µg is available as sugar
coated tablets (Dianette®).
++Dosages & suggested regimens
Finasteride: the recommended dose for male androgenic alopecia is 1 mg
daily. A higher daily dose (5 mg) is used for the treatment of benign prostatic
hyperplasia but does not increase efficacy in hair loss.
Dutasteride: the recommended dose for benign prostatic hyperplasia is 0.5 mg
daily and this dose has also been found to be effective in male androgenic
alopecia. A placebo-controlled study reported that this dose had superior
effects on hair growth and hair count to finasteride. Capsules should be
swallowed whole and not chewed or opened, as contact with the contents
may cause irritation of the oropharyngeal mucosa.
The onset of effect of these agents in male androgenic alopecia is slow and
it usually takes 6 months to stabilize hair loss. Treatment arrests the progression
of disease, but regrowth is partial at best and continued treatment is required
to sustain benefit. If treatment is stopped, the beneficial effects begin to reverse
by 6 months and return to baseline by 9–12 months. At the recommended
dose, finasteride has been shown to improve the anagen (growing phase)
follicle count in males with vertex baldness while those given placebo lost
anagen hair. The majority of males continue to benefit from long-term
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Antiandrogens
treatment (up to 10 years). Adverse effects are uncommon. Efficacy in females
with androgenic alopecia is controversial. No adjustment in dosage is necessary
in renal impairment or in the elderly. Finasteride has a much shorter half-life
than dutasteride.
Flutamide: low doses of 125–250 mg daily are effective for hirsutism.
Dosages of up to 750 mg have been used (i.e. the recommended dose for
prostate cancer). Treatment may be given with a combined OCP and in a
reverse sequential regimen as below.
Bicalutamide: low doses of 25 mg daily for treatment of hirsutism.
Spironolactone: a low starting dose of 25–50 mg daily is recommended
to reduce side-effects, followed by dose increases up to 200 mg daily as
maintenance therapy. (Doses of up to 400 mg daily are used in oedema and
ascites.) Medication should be taken with food to aid absorption.
Drospirenone: the combined OCP preparation Yasmin® is taken once daily
for 21 days, followed by a 7-day tablet free interval.
Cyproterone acetate: for the treatment of hirsutism and female pattern hair
loss, 50 mg daily is usually sufficient, although up to 100 mg/d can be used.
Side-effects are dose dependent so the lowest effective dose is advisable. To
prevent pregnancy and minimize menstrual irregularities it should be taken
daily with the first 10 pills of a combined OCP, i.e. reverse sequential regimen.
Co-cyprindol is taken once daily for 21 days, followed by a 7-day tablet free
interval when a withdrawal bleed should occur.
++Baseline investigations, considerations & monitoring
• Females who are overweight or obese (body mass index [BMI] ≥30) should
be advised to lose weight as this may improve androgen related symptoms.
• Androgen profile, cortisol and pelvic ultrasound scan in females with severe/
progressive hirsutism or acne – especially if associated with menstrual
disturbance.
• Pregnancy should be excluded before starting oral antiandrogen therapy.
Finasteride/dutasteride
• Serum prostate specific antigen (PSA).
• Prostate evaluation by urologist for older males.
• Monitoring: check PSA values regularly and refer to individual’s baseline
value. PSA usually falls with treatment. Any increase in PSA level may
indicate the presence of prostate cancer and needs further evaluation even
if within the normal range. PSA levels should return to baseline within 6
months of discontinuing treatment.
Flutamide/bicalutamide
• Baseline: FBC (CBC), urea and electrolytes, LFTs.
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Antiandrogens
• Monitoring: LFTs monthly for first 4 months, then 3-monthly. Discontinue if
alanine aminotransferase (ALT) increases to twice upper limit of
normal. Monitor methaemoglobin levels in patients susceptible to the
effects of hypoxia.
Spironolactone
• Baseline: BP, weight and BMI.
• FBC, urea and electrolytes.
• Monitoring: FBC, urea and electrolytes after 2 weeks and after dose
increases; discontinue if hyperkalaemia occurs.
Drospirenone (Yasmin®)
• Baseline: BP, weight and BMI.
• Check medical eligibility criteria for combined OCP.
• The risk of venous thromboembolism (VTE) should be assessed (personal or
close family history) as the risk of VTE may be increased in females taking
drospirenone than in those taking other low dose combined OCPs (see
below).
• Start treatment on the first day of the menstrual period.
• Routine monitoring as for OCP: includes review after 3 months then every
6–12 months with measurement of BP and assessment of new risk factors.
Cyproterone acetate as co-pyrindiol (Dianette®)
• Baseline: BP, weight and BMI.
• Check medical eligibility criteria for combined OCP.
• The risk of VTE should be assessed (personal or close family history) as VTE
occurs more frequently in females taking co-cyprindiol than in those taking
low dose combined OCPs (see below).
• Start treatment on the first day of the menstrual period.
• Monitoring as for OCP (see Drospirenone).
Cyproterone acetate (high dose)
• As above with baseline and regular laboratory monitoring (FBC, urea and
electrolytes, glucose, LFTs).
++Contraindications
All antiandrogens are contraindicated in pregnancy. (See pregnancy &
preconception)
Flutamide/bicalutamide:
• Severe hepatic disease.
• Spironolactone:
• Hyperkalaemia and severe renal impairment.
• Postural hypotension.
• Addison’s disease.
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Antiandrogens
• Drospirenone (Yasmin®):
• Contraindications to combined OCP.
• Renal or liver impairment.
• Adrenal insufficiency.
• Cyproterone acetate as co-pyrindiol (Dianette®):
• Contraindications for combined OCP including personal or close family
history of VTE.
• Cypropterone acetate (high dose):
• Meningioma or past history of meningioma.
• Severe depression.
++Cautions
• Finasteride/dutasteride:
• Although the overall risk of prostate cancer is decreased, there is an
increased risk of high grade disease and PSA tests are more difficult to
interpret.
• Flutamide/bicalutamide:
• Cardiac disease.
• Hepatic impairment – closer monitoring needed.
• Renal impairment.
• Spironolactone:
• Elderly.
• Renal impairment, diabetes mellitus.
• Porphyria.
• Patients suffering from menstrual abnormalities or breast enlargement.
• Drospirenone:
• As for combined OCP including diabetes, hypertension, age over 35 years,
obesity and those at risk of thromboembolic disease, depression. All
combined OCPs are associated with an increased risk of VTE, the size of
this risk is related to the dose of oestrogen and the progestagen. The risk
of a VTE is highest during the first year of treatment or when switching/
restarting after a pill free period of at least 1 month. Epidemiological
studies have shown that the incidence of VTE for combined OCPs
containing 30–35 µg ethinyloestradiol and drospirenone, cyproterone
acetate, gestodene and desorgestrel are similar and about 50–80% higher
than for combined OCPs with levonorgestrel.
• Increased risk of hyperkalaemia (in renal impairment, hepatic impairment
and adrenal insufficiency).
• Cyproterone acetate as co-pyrindiol (Dianette®):
• As for combined OCP (see above).
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Antiandrogens
++Important drug interactions
• Finasteride and dutasteride: combination therapy with an alpha blocker,
especially tamsulosin may precipitate cardiac failure.
• Dutasteride: verapamil, diltiazem, isoniazid, and macrolide antibiotics can
increase dutasteride serum concentrations.
• Flutamide: corticosteroids delay its metabolism; avoid concomitant
administration of potentially hepatotoxic drugs, excessive alcohol
consumption, concomitant administration with theophylline – increases
theophylline plasma concentration. It also enhances the anticoagulant
effect of warfarin.
• Bicalutamide: inhibits cytochrome P450 (CYP450) 3A4 and should be used
with caution with other drugs which are metabolized by this enzyme system,
e.g. ciclosporin, cimetidine, calcium channel blockers. It also enhances the
anticoagulant effect of warfarin.
• Spironolactone: due to the drug’s diuretic actions, there is an increased risk
of hyponatraemia with chlorpropamide and hyperkalaemia with potassium
sparing diuretics, ciclosporin, trimethoprim, non-steroidal anti-inflammatory
drugs (NSAIDs) and tacrolimus. The nephrotoxicity of drugs such as NSAIDS
may be increased and excretion of digoxin and lithium reduced, so closer
therapeutic monitoring is required.
• Drospirenone: may worsen hyperkalaemia (see Spironolactone). Drug
interactions are also relevant to the oestrogenic component in Yasmin®
and agents that induce CYP3A4 may increase metabolism of oestrogen and
cause loss of efficacy (see formulary for full prescribing information).
• Cyproterone acetate: oral antidiabetic drug or insulin requirements may
change. Drugs interactions are also relevant to the oestrogenic component
in Dianette® as for Yasmin® (see above and consult full prescribing
information).
++Adverse effects & their management
Finasteride/dutasteride
• Infertility: there have been sporadic reports of infertility and/or poor seminal
quality, but in some cases patients had additional risk factors for infertility.
Normalization or improvement of seminal quality has been reported after
discontinuation of finasteride.
• Sexual adverse effects: in a placebo-controlled trial, a slight increase in the
incidence of sexual adverse effects such as decreased libido, impotence and
ejaculatory dysfunction was reported with finasteride. These adverse effects
gradually disappeared during prolonged treatment. However, persistence
of decreased libido and erectile dysfunction after discontinuation has been
reported in post-marketing data. The risk of sexual dysfunction is slightly
greater in males taking dutasteride compared with finasteride.
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Antiandrogens
• Breast cancer has been reported in males taking finasteride and dutasteride.
Physicians should advise patients to report any changes in their breast tissue
such as lumps, pain, gynaecomastia or nipple discharge.
• Cutaneous adverse effects include rash and pruritus, urticaria, localized
oedema, angioedema, alopecia (primarily body hair loss) and hypertrichosis.
Flutamide/bicalutamide
• Hepatotoxicity ranges from mild transaminitis and jaundice to hepatic
necrosis and encephalopathy. It may be less frequent with bicalutamide
than flutamide. Careful monitoring is required with early discontinuation
if LFTs are deranged.
• Sexual adverse effects are common with non-steroidal antiandrogens
including loss of libido, gynaecomastia, breast tenderness and galactorrhoea.
Dry skin, pruritus and flushing may occur.
• Gastrointestinal adverse effects are common and include nausea and
dyspepsia.
• Haematological adverse effects include anaemia and very rarely
methaemoglobinaemia (flutamide).
• Cutaneous adverse effects including photosensitivity and a systemic lupus
erythematosus-like syndrome have been described.
Bicalutamide: appears to have fewer side-effects than flutamide at the higher
doses used in the treatment of prostate cancer.
Spironolactone
• Hyperkalaemia is dose related and more common in the elderly and those
with renal impairment or cardiac impairment. It may lead to arrhythmia
and cardiovascular collapse. Review other medication (see Important drug
interactions) and discontinue if necessary.
• Non-specific side-effects such as fatigue, headache and dizziness are common.
• Gastrointestinal adverse effects include gastritis and an increased risk of
gastroduodenal bleeding (dose related).
• Sexual adverse effects include gynaecomastia, breast tenderness, loss
of libido and alteration in voice pitch. These are usually reversible on
discontinuation but in rare instances breast enlargement and voice change
may persist. Menstrual irregularities are common with doses above 100 mg
daily and may be improved by combination with an OCP or cyclical therapy
(days 4–21 of menstrual cycle).
• Cutaneous adverse effects include pruritus, alopecia, immediate type
hypersensitivity and severe cutaneous adverse reactions (DRESS and
Stevens–Johnson syndrome).
• Other adverse effects include osteomalacia, agranulocytosis, eosinophilia,
thrombocytopenia and hyponatraemia.
Carcinogenicity has not been established in large epidemiological studies,
though isolated reports have raised concerns especially when long-term
treatment is considered in young females.
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Antiandrogens
Drospirenone (Yasmin®)
• Combined oral contraceptive adverse events: arterial and venous
thromboembolism, hypertension, weight gain, depression, headache and
melasma.
• Hyperkalaemia is a potential adverse effect due to the drug’s potassium
sparing diuretic actions, but large studies in healthy female users have not
shown this metabolic abnormality.
Cyproterone acetate as co-pyrindiol (Dianette®)
• Combined oral contraceptive adverse effects (see above).
Cyproterone acetate (high dose)
• Cardiovascular adverse effects include arterial and venous thromboembolism.
• Hepatotoxic adverse effects include hepatitis, jaundice and liver tumours
(benign and malignant).
• Sexual adverse effects include decreased libido, erectile dysfunction,
reversible inhibition of spermatogenesis, gynaecomastia, galactorrhoea and
hot flushes.
• Metabolic adverse effects include changes in body habitus (central obesity).
• Neurological adverse effects include meningiomas (at doses of 25 mg daily
and above), depression.
• Other adverse effects include anaemia, osteoporosis, fatigue and lassitude.
++Use in special situations
Pregnancy & pre-conception
FDA pregnancy categories:
Bicalutamide, cyproterone acetate, drospirenone, dutasteride, finasteride: X.
Flutamide: D.
Spironolactone: C.
Antiandrogens are contraindicated during pregnancy due to the risk of
feminization of the male fetus. Small amounts of finasteride/dutasteride
have been detected in the semen of males taking this medication. It is not
known whether a male fetus may be adversely affected by in utero exposure
to the semen of a male treated with finasteride or dutasteride, but condom
use is advised. Likewise, it is advised that pregnant females should not handle
crushed or broken tablets.
Finasteride/dutasteride have been reported to adversely affect sperm
counts and quality in healthy males and an impairment of male fertility cannot
be excluded. Flutamide and bicalutamide have both been shown to affect
adversely male fertility.
Lactation
Antiandrogens are contraindicated during breastfeeding. Canrenone, the
principal metabolite of spironolactone, has been detected at low levels in
breast milk, so an alternative method of infant feeding should be instituted.
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Antiandrogens
Cyproterone acetate and drospirenone (Yasmin®) may lead to a reduction
in the volume of milk produced and to a change in its composition. Minute
amounts of these active substances are excreted with the milk. These amounts
may affect the child, particularly in the first 6 weeks post-partum.
Children
Antiandrogen therapy is not relevant in paediatric dermatology as the skin
disorders they are used to treat do not occur before puberty . Spironolactone is
licensed for non-dermatological indications.
++Essential patient information
• Females should be advised of the need to avoid pregnancy during
antiandrogen therapy.
• Counselling for the risks and benefits of combined hormonal contraception
for Yasmin® and Dianette®.
With acknowledgements to Ekaterina P. Burova, author of this chapter in
the 1st edition, and William H. Eaglstein who reviewed this chapter from an
international perspective.
++Further reading
Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for
treatment of acne. Cochrane Database Syst Rev. 2012;7:CD000425.
Banka N, Bunagan K, Shapiro J. Pattern hair loss in men. Dermatol Clin
2012;31(1):129–40.
Blume-Peytavi U, Hahn S. Medical treatment of hirsuitism. Dermatol Therapy
2008;21:329–39.
Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone versus
placebo or in combination with steroids for hirsuitism and/or acne. Cochrane
Database Syst Rev 2009;2:CD000194.
Gubelin Harcha W, Barboza Martinez J, Tsai TF, et al. A randomized active
and placebo-controlled study of the efficacy and safety of different doses of
dutasteride versus placebo and finasteride in the treatment of male subjects
with androgenic alopecia. J Am Acad Dermatol 2014;70:489–98.
Rathnayake D, Sinclair R. Innovative use of spironolactone as an antiandrogen
in the treatment of female pattern hair loss. Dermatol Clin 2010;28(3):611–18.
Rossi A, Cantisani C, Scarnò M, Trucchia A, Fortuna MC, Calvieri S. Finasteride
1 mg daily administration on male androgenetic alopecia in different age
groups: 10-year follow-up. Dermatol Therapy 2011;24(4):455–61.
Sinclair R, Patel M, Dawson TL Jr, et al. Hair loss in women: medical and
cosmetic approaches to increase scalp hair fullness. Br J Dermatol 2011;165
(Suppl. 3):12–8.
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Antibiotics Commonly
Used for Skin Infections
Hui Min Liew, Victoria J. Hogarth & Roderick J. Hay
Antibiotics are drugs with therapeutic activity against living organisms, the term
being usually reserved for drugs active against bacteria. They are commonly
described as either bacteriostatic or bactericidal, depending on whether at any
given concentration they inhibit or kill the bacteria. Site of infection, strain
of organism and drug concentration are all important in determining this
characteristic. This chapter is concerned with the antibiotics most commonly
used in dermatology, including broad- and narrow-spectrum drugs. One of the
problems dominating antibiotic usage is the rising prevalence of resistance
among bacteria, either because of intrinsic drug resistance or acquired
resistance due to mutation or transfer of plasmid based resistance genes.
Penicillins
++Classification & mode of action
Penicillins are bactericidal because they inhibit bacterial cell wall synthesis
leading to death of the micro-organism. The basic structure of a penicillin
consists of a thiazolidine ring, a β-lactam ring and a variable side-chain. They
are usually divided into penicillinase-sensitive (e.g. benzylpenicillin/penicillin G
and phenoxymethlypenicillin/penicillin V) or penicillinase-resistant penicillins
(e.g. methicillin, flucloxacillin), broad-spectrum penicillins, antipseudomonal
penicillins and mecillinams. All penicillins are readily and actively secreted by
the renal tubules and most are eliminated, almost completely unchanged, in
the urine.
++Indications & dermatological uses
• Penicillins are first-line drugs for infections by Staphylococcus aureus,
Streptococcus pyogenes group A, Treponema pallidum and meningococcal
septicaemia, as well as yaws, actinomycosis and diphtheria. Most S. aureus
strains are resistant to benzylpenicillin because they produce penicillinases.
• Flucloxacillin is resistant to degradation by this enzyme and therefore
is effective against penicillin-resistant staphylococci. Penicillin V (also
known as phenoxymethylpenicillin) has similar antibacterial properties
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Antibiotics Commonly Used for Skin Infections
to benzylpenicillin, but it is less active and produces variable plasma
concentrations.
In dermatology, flucloxacillin is indicated for pyodermas such as extensive
impetigo, early furunculosis and erysipelas and cellulitis. If the patient is acutely
unwell, i/v penicillins, e.g. piperacillin, should be considered. Oral penicillin V
has a role in prophylaxis against recurrent streptococcal cellulitis in patients
with lymphoedema.
Infection with S. aureus strains resistant to methicillin (MRSA) and to
flucloxacillin has become a serious concern as it is endemic in many hospitals
and is also becoming a problem in the community setting. The hospital-acquired
strains (HA-MRSA) show multiple drug resistance, whereas community-acquired
strains (CA-MRSA) usually show resistance to a smaller range of penicillins, e.g.
methicillin. Treatment of MRSA is guided by the sensitivity of the infecting
strain and local hospital eradication policy regime.
Strains of CA-MRSA, unlike HA-MRSA, usually carry a gene encoding the
Panton–Valentine leukocidin (PVL) toxin. This is a virulence determinant and is
associated with multiple skin and soft tissue infections such as abscesses. PVL
positive strains may also occur without methicillin resistance, but even then
flucloxacillin is usually ineffective and may increase PVL production. In such
cases rifampicin and clindamycin are usually recommended.
++Formulations/Presentation
• Penicillin V: tablets (250 mg); oral solution (125 mg/5 mL or 250 mg/5 mL).
• Benzylpenicillin sodium powder: 600 mg vials.
• Flucloxacillin: capsules (250 mg or 500 mg); oral solution (125 mg/5 mL
or 250 mg/5 mL); injection either i/m, slow i/v or i/v infusion (250 mg or
500 mg vial).
++Dosages & suggested regimens
Penicillin V: in adults, 500 mg every 6 hours, can be increased up to 1 g every 6
hours in severe infections. In children up to 1 year, 62.5 mg every 6 hours; 1–6
years, 125 mg every 6 hours; 6–12 years, 250 mg every 6 hours. If the infection
is severe, the dose can be increased up to 12.5 mg/kg every 6 hours.
Benzylpenicillin: in adults, 0.6–1.2 g every 6 hours, by i/m injection, slow i/v
injection or infusion. Increased dosages (by i/v route only) and frequency of
injection may be indicted in severe infection. In children 1 month–18 years, 25
mg/kg every 6 hours (see children's formulary for further information in severe
infections).
Flucloxacillin: in adults, 250–500 mg every 6 hours, at least 30 minutes before
food or 2 hours after food, or by i/m injection, usually for 7 days. By slow i/v
injection or by i/v infusion, 0.25–2 g every 6 hours. In children 1 month–2 years,
62.5–125 mg every 6 hours; 2–10 years, 125–250 mg every 6 hours.
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For these short half-life penicillins, high peaks are much less important than
duration of exposure, so for parenteral administration, continuous i/v infusion
may optimize therapy.
++Baseline investigations & considerations
No investigations are required. Patients should be asked about previous
hypersensitivity reactions to b-lactam antibiotics (see Special point).
++Monitoring
Monitoring is not necessary unless the patient is on a prolonged course of
flucloxacillin or is known to have renal or hepatic impairment.
++Contraindications
Penicillins are contraindicated in patients with known penicillin or b-lactam
antibiotic hypersensitivity (see Special point).
++Cautions
• Chronic renal impairment: reduce dose of flucloxacillin if the estimated
glomerular filtration rate (eGFR) is less than 10 mL/min/1.73 m2 (see Systemic
Therapy & Kidney Disease).
• Hepatic impairment (flucloxacillin).
• Elderly and those with serious underlying disease (increased risk of hepatitis
with flucloxacillin).
++Important drug interactions
There are few significant drug interactions. The following should be noted:
• Neomycin reduces the absorption of penicillin V.
• Oral anticoagulant actions (and INR) can be altered by penicillins, in
particular the broad-spectrum penicillins; close monitoring is required.
• Methotrexate excretion may be reduced by penicillins, increasing the risk
of toxicity.
• Oral typhoid vaccine may be inactivated by penicillins, as other antibiotics.
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++Adverse effects & their management
• Gastrointestinal (GI): minor GI upset and diarrhoea is a common problem,
while antibiotic associated colitis is very rare. The penicillin must be stopped
immediately and treatment given with oral vancomyin or metronidazole.
• Hypersensitivity reactions vary according to the underlying immunological
mechanism (as below). Immediate drug withdrawal is usually needed, and
treatment may be required (e.g. anaphylaxis therapy, corticosteroids). If
further treatment with the antibiotic is essential, drug desensitization may
be considered.
• Immediate type hypersensitivity reactions with urticaria, angioedema and
anaphylaxis may follow parenteral or oral therapy. Serum sickness type
hypersensitivity reactions with fever, arthralgia and rashes can occur.
• Drug rashes are usually morbilliform (‘measles-like’), but a range of drug
eruptions can occur, including Stevens–Johnson syndrome, acute generalized
exanthematous pustulosis and toxic epidermal necrolysis.
• Hepatitis and cholestatic jaundice are very rare idiosyncratic adverse effects,
especially with flucloxacillin. The onset may be delayed for up to 2 months
post-treatment and may persist for months. Risk factors include age over 55
years and duration of therapy over 2 weeks.
• Other very rare reactions include interstitial nephritis, haemolytic anaemia,
leukopenia, thrombocytopenia and coagulation disorders.
++Use in special situations
Pregnancy (FDA Category B)
Penicillins are not known to be harmful in pregnancy.
Lactation
Penicillins are not known to be harmful in lactation. Trace amounts of penicillins
are excreted in human breast milk.
Children
It is safe to use penicillins in children when clinically indicated. The dosing is
according to age and weight.
Elderly
Penicillin V is not known to cause any problems in the elderly but careful note
should be made of concurrent drugs to avoid interactions.
Special point: immediate hypersensitivity
Patients with IgE (immediate type) hypersensitivity to penicillins may be reactive
to the b-lactam ring that is common to all penicillins (including cephalosporins,
carbapenems and monobactrams) or the R-group side-chain that distinguishes
different penicillins from one another. Although early studies reported a
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c­ross-reactivity rate of 5–10% between cephalosporins and penicillin allergy
in patients with IgE mediated penicillin allergy, most penicillin allergic
patients can tolerate third and fourth generation cephalosporins because the
R-side-chain (rather than the b-lactam ring) appears to play the dominant role
in cephalosporin allergy.
The use of in vivo skin tests (skin prick tests and intradermal tests) is well
validated for b-lactam antibiotics. Commercial reagents are available in many
countries, minor determinant mix. In vitro diagnostic immunoassays are
generally more expensive and less specific. Finally, drug provocation testing
may be required to exclude cross-reactivity.
++Essential patient information
Patients should be informed about the side-effect profile of penicillins.
Erythromycin & clarithromycin
++Classification & mode of action
Macrolides, including erythromycin and clarithromycin, are antibiotics
whose structure is based on a large macrocyclic lactone ring. They act by
inhibiting protein synthesis through binding to ribosomes and are mainly
bacteriostatic.
++Indications & dermatological uses
• Erythromycin is the most widely used macrolide. It is active mainly
against Gram-positive organisms such as staphylococci and streptococci.
Staphylococci and streptococci may become erythromycin resistant,
including as many as 50% of staphylococci strains. However, erythromycin
may be active against many penicillin resistant staphylococci. Uses include
staphylococcal and streptococcal pyodermas, especially in penicillin allergic
patients, erythrasma and acne. Macrolides may be more effective than
penicillins for the treatment of cellulitis. Macrolides may also be used for
atypical mycobacterial infections and for Lyme disease and syphilis.
• Clarithromycin is an erythromycin derivative with a slightly greater
activity and greater tissue concentrations. Although not widely used in
dermatology, it is licensed for treatment of skin infections and is also used
for the treatment of atypical mycobacterial infections.
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++Formulations/Presentation
• Erythromycin: 250 mg, 500 mg tablets and capsules, 125 mg/5 mL suspensions
(including sugar-free suspensions).
• Clarithromycin: 250 mg, 500 mg tablets, 125 mg/5 mL suspension, granules
250 mg/sachet.
++Dosages & suggested regimens
Erythromycin: adults and children over 8 years: 250–500 mg every 6 hours or
0.5–1 g every 12 hours; up to 4 g daily in divided doses in severe infections.
Younger children: 1 month–2 years: 125 mg every 6 hours; 2–8 years: 250 mg
every 6 hours. Doses are doubled for severe infections. Lyme disease: 500 mg
four times daily for 14–21 days. By i/v infusion: adult and child severe infections,
50 mg/kg daily by continuous infusion or in divided doses every 6 hours, mild
infections (oral treatment not possible), 25 mg/kg daily.
Clarithromycin: adults and children over 12 years: 250 mg every 12 hours
for 7 days, increased in severe infection up to 500 mg every 12 hours for up
to 14 days. By i/v infusion into larger proximal vein: 500 mg twice daily. For
younger children (1 month–12 years) the dosage depends on body weight:
<8 kg: 7.5 mg/kg twice daily; 8–11 kg: 62.5 mg twice daily; 12–19 kg: 125 mg
twice daily; 20–29 kg, 187.5 mg twice daily; 30–40 mg, 250 mg twice daily.
++Baseline investigations & considerations
No routine investigations/monitoring are required in the absence of renal
impairment.
++Contraindications
• Erythromycin or clarithromycin hypersensitivity.
• Severe hepatic impairment, history of hepatitis caused by macrolides,
cholestasis.
• Clarithromycin is contraindicated in patients with prolonged QT intervals,
ventricular dysrhythmias and hypokalaemia.
++Cautions
Erythromycin
• Maximum dose of 1.5 g daily in severe renal impairment (risk of hearing
loss).
• Avoid in acute porphyria.
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• Neonates under 2 weeks: risk of hypertrophic pyloric stenosis.
• Pre-disposition to QT interval prolongation, therefore caution with
concomitant use of drugs that prolong QT interval and electrolyte
disturbances.
Clarithromycin
• Caution is advised in hepatic impairment as clarithromycin is mainly excreted
by the liver.
• The dosage should be reduced in moderate to severe renal impairment.
++Important drug interactions
Macrolide antibiotics have numerous drug interactions due to inhibitory
effects on the cytochrome P450 (CYP450) 3A4 isoenzyme, and enhancing the
cardiotoxicity of certain drugs. Prescribers are advised to consult an updated
drug formulary.
Macrolides should not be prescribed with the following:
• Antipsychotic drugs including droperidol, pimozide, sertindole.
• Cisapride (no longer available in UK), due to the risk of ventricular
dysrhythmias.
• Ergot alkaloids (unlicensed use for headache), due to increased risk of
ergotism.
• Mizolastine, due to QT prolongation.
• Simvastatin, lovastatin, due to increased risk of myopathy.
Care should be taken if erythromycin or clarithromycin are prescribed with
the following:
• Atorvastatin and pravastatin: a lower dose should be used and patients
monitored carefully for signs of myopathy (muscle pain and weakness).
Other statins that are not metabolized by CYP3A4 (rosuvastatin, fluvastatin)
may carry less risk of myopathy. Measurement of serum creatine kinase (CK)
is helpful as modest elevations (up to five times upper limit of normal) are
common and usually related to exercise. A rise in CK of more than 10 times
above the upper limit of normal can indicate significant myopathy and a risk
of rhabdomyolysis, which is a medical emergency.
• Calcium channel blockers: the risk of hypotension or shock is increased with
erythromycin and clarithromycin. In elderly patients at risk, azithromycin is
the macrolide of choice.
• Ciclosporin (cyclosporine) metabolism may be inhibited, with increased
toxicity (see Ciclosporin).
• Colchicine, due to increased risk of colchicine toxicity (see Colchicine).
• Coumarin anticoagulants (e.g. warfarin), due to increased anticoagulant
effects with risk of serious haemorrhage. Close monitoring of INR is essential.
• Digoxin plasma concentrations are raised with risk of toxicity.
• Methyl prednisolone metabolism may be inhibited.
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• Oral contraceptives: there may be a short-term impairment in the
contraceptive effects of oestrogen-containing pills due to alteration of gut
flora.
• Oral hypoglycaemic agents/insulin: the concomitant use of macrolides and
certain oral hypoglycaemic agents and/or insulin can result in significant
hypoglycemia. Careful monitoring of glucose is recommended.
• Phenytoin, carbamazepine, clozapine and valproate, due to decreased
metabolic clearance and increased plasma levels.
• Theophylline, due to increased plasma theophylline which may cause
nausea, vomiting and seizures.
• Verapamil, due to increased risk of cardiotoxicity
++Adverse effects & their management
Erythromycin
• Cholestatic hepatitis can occur with erythromycin estolate.
• Gastrointestinal: nausea and colicky pains are common, with occasional
vomiting and diarrhoea. Symptoms may be improved by giving a lower dose
(250 mg four times daily).
• Hypersensitivity reactions are rare. They include Stevens–Johnson syndrome
and toxic epidermal necrolysis.
• Reversible hearing loss and tinnitus have been reported after large i/v
doses, and in renal impairment.
• Other effects include pancreatitis, cardiac effects, myasthenia-like syndrome/
exacerbation of myasthenia gravis.
Clarithromycin
The adverse reaction profile is similar to that of erythromycin:
• Hepatitis and cases of fatal hepatic failure have been reported. Advise
patients to stop treatment and contact their doctor if signs and symptoms
of hepatic disease develop.
• Tooth and tongue discolouration, smell and taste disturbances, stomatitis
and glossitis.
• Less commonly: arthralgia, myalgia, headache.
• Very rarely: dizziness, insomnia, nightmares, anxiety, confusion, psychosis,
paraesthesia, convulsions, hypoglycaemia, renal failure, intestinal nephritis,
leukopenia and thrombocytopenia.
Patients who are hypersensitive to clindamycin may also be hypersensitive
to clarithromycin, so caution is required if they are prescribed clarithromycin.
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++Use in special situations
Pregnancy (FDA Category B)
Erythromycin crosses the placenta but is not known to be harmful in pregnancy.
The manufacturers advise avoiding clarithromycin in pregnancy unless the
potential benefit outweighs the risk.
Lactation
Only small amounts of erythromycin are found in breast milk and this is not
known to be harmful. The manufacturers advise avoiding clarithromycin in
lactation unless the potential benefit outweighs the risk.
Children
Both drugs are available in paediatric formulations. Remember the risk of
pyloric stenosis in neonates.
Elderly
Consider underlying renal impairment which may affect drug dosage for
clarithromycin.
Clindamycin
++Indications & dermatological uses
Clindamycin is a lincosamide antibiotic with activity against Gram-positive
cocci and many anaerobes. It has a bacteriostatic effect by inhibiting
bacterial ribosomal translocation. It can be used as an alternative to
macrolides for erysipelas or cellulitis and for infections associated with MRSA.
Topical clindamycin is licensed for use in acne and bacterial vaginosis.
++Formulations/Presentation
Capsules (75 mg, 150 mg), i/m and i/v preparations.
++Dosages & suggested regimens
The usual adult oral dose is 150–300 mg every 6 hours and up to 450 mg every
6 hours in severe infection. The recommended dose of clindamycin in children
is 3–6 mg/kg every 6 hours.
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A regimen of 300 mg clindamycin twice daily and 300 mg rifampicin (see
below) twice daily for 10 weeks has been reported to be effective in the
treatment of hidradenitis suppurativa.
Deep i/m or i/v infusion in 2–4 divided doses/d may be used as an alternative
to oral therapy or in severe infection. Injections containing benzyl alcohol
should be avoided in neonates.
++Baseline investigations & considerations
In neonates and infants being treated for greater than 10 days: LFTs and renal
indices.
++Monitoring
LFTs and renal indices weekly for prolonged therapy (>10 days) in neonates
and infants.
++Contraindications & cautions
• Diarrhoea and colitis.
• Acute porphyria.
++Important drug interactions
• Erythromycin should not be prescribed concurrently as its antibacterial
actions may be impaired by clindamycin.
• Neuromuscular blocking agent effects may be enhanced and the effects of
cholinesterase inhibitors prolonged.
• Oral typhoid vaccine is inactivated by antibacterials.
++Adverse effects & their management
• Clostridium difficile-associated diarrhoea (CDAD) is the most frequent cause
of pseudomembranous colitis, which is the most serious common adverse
effect of clindamycin. Although CDAD can occur with almost all antibiotics
(including b-lactams), it is classically linked to clindamycin use. Symptoms
may develop several weeks after ceasing therapy. The drug should be
discontinued immediately if marked diarrhoea or colitis develops (severe
abdominal pains with passage of blood and mucus). If allowed to progress,
it may lead to toxic megacolon, peritonitis and fatal septicaemic shock.
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The disease is likely to follow a more severe course in elderly or debilitated
patients. Diagnosis can be confirmed by colonoscopic demonstration of
pseudomembranous colitis and culture of the stool for C. difficile or assay of the
stool specimen for C. difficile toxin. Treatment is usually with oral vancomycin
125–500 mg four times a day for 7–10 days. Hypertoxin producing strains of C.
difficile can be refractory to antimicrobial therapy and may require colectomy.
Probiotics taken for the duration of antibiotic treatment and the following
2 weeks may have a protective effect. CDAD must be considered in all patients
who present with diarrhoea following antibiotic use.
Other adverse effects include the following:
• Jaundice and hepatitis.
• Taste disturbance, oesophagitis, oesophageal ulceration.
• Hypersensitivity reactions including urticaria, anaphylactoid reactions.
• Dermatological: generalized mild–moderate morbilliform-like skin rashes
are the most frequently reported rashes. Rare cases of erythema multiforme,
Stevens–Johnson syndrome, pruritus, vaginitis, exfoliative or vesiculobullous
dermatitis and toxic epidermal necrolysis have been reported.
• Induration, pain and abscess formation after i/m injection; thrombophlebitis
after i/v injection.
• Haematological adverse effects include eosinophilia, neutropenia and
thrombocytopenia.
++Use in special situations
Pregnancy (FDA Category B)
Clindamycin is not known to be harmful in pregnancy.
Lactation
It is excreted in breast milk, but the amount is probably too small to be
significant.
Children
Licensed from aged above 1 month in the UK. A syrup formulation containing
75 mg clindamycin/5 mL may be obtained from outside the UK.
Elderly
Clindamycin should be used with caution in frail elderly patients due to their
increased susceptibility to complications of CDAD.
++Essential patient information
Patients should be fully informed about the risk of diarrhoea and colitis
and advised to discontinue the drug immediately and to contact a doctor if
symptoms develop. Capsules should be swallowed with a glass of water.
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Rifampicin
Rifampicin is a complex, synthetically modified antibiotic of the rifamycin
group and has a concentration dependent, prolonged postantibiotic effect.
It is bactericidal and very effective against Mycobacterium tuberculosis, many
atypical myobacteria and Gram-positive cocci such as S. aureus.
++Indications & dermatological uses
Rifampicin is always used in combination with other antimicrobials, such as
clarithromycin or clindamycin, to prevent the rapid emergence of resistant
strains. It is licensed for use in the following infections:
• Tuberculosis: for all forms of disease in combination with other drugs.
• Atypical mycobacterial infections.
• Leprosy: in combination with at least one other active antileprosy drug.
• Brucellosis.
• Legionnaires’ disease.
• Serious staphylococcal infections.
Dermatological uses include PVL-positive S. aureus. Benefit has also been
reported in recalcitrant pustular/follicular diseases including hidradenitis
suppurativa, folliculitis de calvans/tufted folliculitis.
Rifampicin is also used in asymptomatic carriers to eliminate Neisseria
meningitidis and Haemophilus influenzae.
++Formulations/Presentation
Rifampicin is available as 150 mg and 300 mg capsules and a 100 mg/5 mL
syrup.
++Dosages & suggested regimens
In adults it is usual to prescribe 450–600 mg/d as a single dose before
breakfast. Concomitant antacid administration may reduce absorption,
so rifampicin should be given at least 1 hour before the ingestion of
antacids.
++Baseline investigations & considerations
Liver biochemistry (LFTs) may be checked at baseline but monitoring is
generally not necessary during treatment. Rifampicin may inhibit standard
microbiological assays for serum folate and vitamin B12, so alternative assay
methods should be considered.
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++Contraindications
Severe liver impairment or jaundice.
++Cautions
• Liver impairment: a reduced dose is indicated due to impaired elimination
with regular monitoring of liver enzymes every 2–4 weeks during therapy.
• Alcohol dependence: regular monitoring of liver enzymes is advised.
++Important drug interactions
Rifampicin is a potent inducer of certain CYP450 enzymes. Concurrent
administration of rifampicin with other drugs that are also metabolized
through these pathways may accelerate the metabolism and reduce the
activity of these other drugs with loss of therapeutic effectiveness. The number
of potential interactions is large and includes the following:
• Antiarrhythmics, calcium channel blockers and cardiac glycosides (digoxin).
• Oestrogens, progestogens in hormonal contraceptives and hormone
antagonist (antioestrogens, e.g. tamoxifen). Advise patients to use
alternative, non-hormonal methods of birth control during rifampicin
therapy.
• Antipsychotics, anxiolytics, barbiturates and anticonvulsants (phenytoin).
• Anticoagulants (e.g. coumarins).
• Azole antifungals.
• Antiretrovirals (e.g. saquinavir, indinavir, efavirenz, amprenavir, nelfinavir,
atazanavir, lopinavir, nevirapine). When rifampicin is given concomitantly
with the combination saquinavir/ritonavir, the potential for hepatotoxicity
is increased. Therefore, concomitant use of this drug combination is
contraindicated.
• Antibacterials (e.g. clarithromycin, dapsone, doxycycline, fluoroquinolones).
• Corticosteroids.
• Oral hypoglycaemic agents for diabetes. Diabetes may become more
difficult to control.
• Immunosuppressive agents (e.g. ciclosporin [cyclosporine], sirolimus,
tacrolimus).
• Thyroid hormone (levothyroxine).
• Statins metabolized by CYP3A4 (e.g. simvastatin).
• Theophylline.
++Adverse effects & their management
Rifampicin is generally regarded as a relatively safe drug, but the following
adverse reactions have been described:
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• Cutaneous adverse effects that are mild and self-limiting consist of flushing
and pruritus with or without a rash. Urticaria and more serious cutaneous
adverse drug reactions are uncommon. Exfoliate dermatitis, bullous
dermatoses, erythema multiforme/Stevens–Johnson syndrome and vasculitis
have been reported rarely.
• Gastrointestinal adverse effects are common and consist of anorexia,
nausea, vomiting, abdominal discomfort and diarrhoea.
• Hepatitis is usually characterized by transiently elevated transaminases.
Hyperbilirubinaemia can occur in the early days of treatment due to
competition between rifampicin and bilirubin for hepatic excretion.
• Thrombocytopenia with or without purpura may occur, and is in association
with intermittent therapy. Eosinophilia, leukopenia and agranulocytosis
have also been reported.
• A flu-like syndrome consisting of episodes of fever, chills, headache,
dizziness and bone pain has mainly been reported with intermittent or
irregular therapy and may represent drug hypersensitivity. Anaphylaxis has
also been described.
• Red-orange discolouration of the urine, sweat, sputum and tears is common
and may lead to permanent staining of soft contact lenses.
++Use in special situations
Pregnancy (FDA Category C)
Animal data indicate that there is a potential risk to the fetus but there is no
confirmatory information in humans. Caution is therefore advised but depending
on the condition under treatment, the benefits may outweigh any risk.
Lactation
Rifampicin is excreted in breast milk at low concentrations. The amounts are
considered too small to be harmful.
Children
Rifampicin is used in special situations such as tuberculosis in childhood.
++Essential patient information
• The drug should be stopped immediately if purpura develop and should not
be given again.
• Patients should be advised how to recognize signs of liver disorders, and to
stop treatment immediately and seek advice if symptoms such as persistent
nausea, vomiting, malaise, jaundice or bruising develop.
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Fluoroquinolones
The fluoroquinolones or 4-quinolones are antibiotics whose principal use in
dermatology is the treatment of Gram-negative infections. Their mode of
action is by inhibition of DNA synthesis. Generally only one of these agents,
ciprofloxacin, is used in dermatology. Other fluroquinolones include norfloxacin
and ofloxacin.
++Indications & dermatological uses
Ciprofloxacin is used in the treatment of lower respiratory tract, GI, urinary
tract and genital tract infections. In dermatology, it is used for Gram-negative
infections of the skin and soft tissue and Gram-negative folliculitis.
++Formulations/Presentation
Ciprofloxacin is available in 100 mg, 250 mg, 500 mg and 750 mg tablets, a
strawberry flavoured suspension of 250 mg/5 mL and powder for i/v infusion.
++Dosages & suggested regimens
For most skin infections the usual dose is 250–750 mg twice daily for 7–14 days,
depending on severity. For unresponsive cellulitis the higher dose of 750 mg
twice daily is used. Ciprofloxacin is well absorbed after oral administration and
rarely needs to be given parenterally.
++Monitoring
Routine monitoring is not essential.
++Contraindications
Patients with known hypersensitivity to quinolones.
++Cautions
Lower dosages are used in patients with renal impairment (see Systemic
Therapy & Kidney Disease).
Use with caution in patients with cardiac disease due to possible QT interval
prolongation.
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++Important drug interactions
• Drugs causing QT interval prolongation.
• Ciprofloxacin inhibits the enzyme CYP1A2 and thus may cause increased
serum concentration of concomitantly administered drugs metabolized by
this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine,
duloxetine). Co-administration of ciprofloxacin and tizanidine (a muscle
relaxant) is contraindicated.
• Methotrexate excretion may be inhibited, leading to toxicity
++Adverse effects & their management
• Hypersensitivity and anaphylactic reactions have been described.
• Phototoxicity may occur, so avoid excess sunlight or artificial ultraviolet (UV)
exposure.
• QT interval prolongation may occur in patients with cardiac disorders,
electrolyte imbalance (hypokalaemia, hypomagnesaemia) and drugs
therapy (see above).
• Tendonitis and tendon rupture (especially the Achilles tendon) may occur
even within the first 48 hours of treatment. Inflammation and rupture
can also occur up to several months after therapy. The risk is increased in
elderly patients and those receiving corticosteroids. The drug should
be discontinued at any sign of tendonitis and care taken to rest the
affected limb.
• Seizure threshold may be lowered in predisposed patients with CNS
disorders. Polyneuropathy, depression and psychosis have been reported.
• Haemolytic reactions may occur in patients with glucose-6-phosphate
dehydrogenase deficiency.
• Hepatitis ranging from mildly abnormal LFTs to hepatic necrosis and lifethreatening hepatic failure.
++Use in special situations
Pregnancy (FDA Category C)
Effects on immature cartilage have been observed in animal studies, so as a
precaution, it is preferable to avoid in pregnancy.
Lactation
Ciprofloxacin is excreted in breast milk and should not be used in lactation due
to the potential risk of joint damage.
Children
Ciprofloxacin is associated with an increased risk of musculoskeletal disorders
in children and is therefore not recommended except in severe infections.
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Elderly
Elderly patients and females may be more sensitive to QT prolonging
medications. Therefore, caution should be taken when using ciprofloxacin in
these populations.
++Essential patient information
Advise about signs and symptoms of tendonitis and hepatitis.
++Further reading
Breathnach SM, Smith CH, Chalmers RJG, Hay RJ. Rook’s Textbook of
Dermatology: Systemic Therapy. 8th edn. Wiley-Blackwell, 2010, pp. 74.1–74.53.
Carter EL. Antibiotics in cutaneous medicine: an update. Semin Cutan Med Surg
2003;22:197–211.
Kilburn SA, Featherstone P, Higgins B, Brindle R. Interventions for cellulitis and
erysipelas. Cochrane Database Syst Rev 2010;6:CD004299.
Rayner C, Munckhof WJ. Antibiotics currently used in the treatment of infections
caused by Staphylococcus aureus. Intern Med J 2005;35(Suppl. 2):S3–16.
Stevens DL, Ma Y, Mclndoo E, Wallace RJ, Bryant A. Impact of antibiotics on
expression of virulence-associated exotoxin genes in methicillin-sensitive and
methicillin-resistant Staphylococcus aureus. J Infect Dis 2007;195:202–11.
Wispelwey B. Clinical implications of pharmacokinetics and pharmacodynamics
of fluoroquinolones. Clin Infect Dis 2005;41(Suppl. 2):S127–35.
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Antifungals
Marie-Louise Daly, Victoria J. Hogarth, Hui Min Liew,
Mary Sommerlad, & Rachael Morris-Jones
Systemic antifungal drugs are highly effective in treating superficial
­dermatomycoses acquired in temperate climates. Unfortunately, tropical and
deep fungal infections often remain recalcitrant to treatment despite high dose
prolonged therapy with newer agents. Topical treatment is often adequate
for localized superficial yeast and dermatophyte infection, but nail and scalp
infections usually require systemic therapy to enable adequate delivery of drug
to the ­infected hair shafts and nail plates.
Fungi are broadly divided into moulds and yeasts. A mould is made up of
multinucleate filaments called hyphae, which can be divided by septae and
grow continuously from their apical tip. Yeasts are unicellular and usually oval
in shape. They mainly replicate by budding. Some fungi including Candida and
dimorphic species (such as Aspergillus) are able to switch between producing
hyphae and yeast forms depending on the environment. Hyphal forms are
­usually necessary for invasion of cells and tissue, whereas yeast forms appear
to be important for dissemination to distant sites.
The plasma membrane of fungal cells contains ergosterol rather than
cholesterol as in mammalian cells and the majority of antifungal drugs exert
their selective effects by interfering with the enzymatic pathway of ergosterol
biosynthesis (see Table 1). However, some of these enzymes are also involved
with cholesterol metabolism. The majority of antifungal drugs are fungistatic
(­inhibiting fungal cell growth) at concentrations achievable at sites of infection.
Only a minority have the advantage of being fungicidal (kill fungal cells), which
enables more effective clearance of fungal infections with a shorter course of
treatment, and less evolution of drug resistance.
The main categories of antifungal drugs are listed in Table 1, which
­summarizes their classification and mechanism of action (see also Figure 1).
The systemic antifungal drugs used in dermatology (terbinafine, azoles and
­griseofulvin) are discussed in more detail.
Patients at risk from superficial fungal infections include children (tinea
­capitis), the elderly (onychomycosis), the immunosuppressed, animal handlers
(zoophilic tinea corporis), athletes (tinea pedis, tinea cruris) and those with
diabetes (candidiasis). Human immunodeficiency virus (HIV) infection may
­predispose individuals to more severe and more frequent infections, particularly
onychomycosis, which may fail to respond to conventional doses of antifungals.
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TABLE 1 Classification and mechanism of action of antifungal drugs
Group
Examples
Mode of action
Main indications
Azoles
Imidazoles
Clotrimazole
Econazole
Ketoconazole
Miconazole
Inhibit C-14 sterol
demethylase via
cytochrome P450
leading to a reduction
in ergosterol
Tinea infections
Candida skin
infections
Vaginal candidiasis
Tioconazole
Triazoles
Onychomycosis
Itraconazole
Fluconazole
Oropharyngeal
candidiasis
Vaginal candidiasis
Sporotrichosis
Tinea skin infections
Onychomycosis
Voriconazole
Posaconazole
Fusarium, Mycetoma,
chromoblastomycosis
Coccidiodomycosis
Scedosporium,
Candida
Allyamines
Terbinafine
Naftifine
Inhibit squalene
­epoxidase causing
squalene accumulation
Tinea infections
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Inhibit (1-3)-b- dglucan synthase a
component of fungal
cell wall
Invasive aspergillosis
Invasive candidiasis
Morpolines
Amorolfine
Inhibits 14 reductase
epoxidase causing
squalene accumulation
Dermatophyte
onychomycosis
Polyenes
Amphoteracin B
(Nystatin)
(Natamycin)
Binds to ergosterol in
fungal cell walls and
disrupts membrane
structure
Invasive candidiasis
Invasive aspergillosis
Cryptococcosis
Sporotrichosis
Others
Griseofulvin
Disrupts microtubule
function in nuclear
division
Tinea infections
Onychomycosis
Flucytosine
(5-fluorocytosine)
Inhibits DNA and RNA
synthesis
Cryptococcosis
Invasive candidiasis
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Squalene
Epoxidase
–
Terbinafine
–
Azole antifungals
–
–
Amorolfine
Amorolfine
Squalene epoxide
Lanosterol
Lanosterol 14 demethylase
Δ14-Reductase
Δ7Δ8-Isomerase
14-Demethyl lanosterol
Ergosterol
FIGURE 1 Points of action of antifungal drugs in the pathway of ergosterol
biosynthesis.
AZOLE ANTIFUNGAL DRUGS
++Classification & mode of action
Azole antifungals are a synthetic group of fungistatic agents with a broad
­spectrum of activity. They are based on a 5-member ring structure and c­ lassified
into two groups: imidazoles and triazoles. They bind to the iron atom in the
haem component of lanosterol-14 demethylase (or CYP51A1, P45014DM)
a c­ytochrome P450 enzyme that converts lanosterol to ergosterol, a major
­fungal wall component. This leads to arrested fungal growth. Triazoles have
a higher specificity of binding than imidazoles, leading to increased potency.
­Over-expression of CYP51A1 or impairment of energy dependent facilitated
­diffusion of azoles into fungal cells are mechanisms underlying drug resistance.
Most imidazole antifungal drugs are only formulated for topical use
(clotrimazole, miconazole, econazole) to treat the skin and nails. K
­ etoconazole
is the exception, but is no longer recommended for systemic use due to the
risk of hepatotoxicity. Triazoles (itraconazole, fluconazole, voriconazole,
posaconazole) are used systemically and have a higher specificity against
­
fungal cytochrome P450 (CYP450) than imidazoles and less human toxicity.
Fluconazole has good activity against fungal yeast forms but lacks activity
against moulds, whereas itraconazole has a wider spectrum of action, but less
reliable bioavailability. Vorioconazole and posaconazole are used for invasive
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fungal infections. The adverse effects of voriconazole include hepatitis, hair
loss, nail changes, phototoxicity and squamous cell carcinoma.
The widespread therapeutic and prophylactic use of azole antifungal drugs
has led to an increase in the rate of drug resistance. This can relate to the ability
of some fungal species to switch from yeast to hyphal forms in the presence of
azole drugs.
Itraconazole
Itraconazole is highly lipophilic and well absorbed with a prolonged
half-life. The therapeutic effect in the skin is achieved by passive diffusion into
basal keratinocytes, a high rate of excretion in sebum and to a lesser degree,
excretion in sweat. Extensive tissue (protein) binding in skin and hair has been
demonstrated, so the active drug persists for several weeks after stopping
therapy.
++Indications & dermatological uses
The licensed dermatological indications for itraconazole are:
• Dermatophytoses caused by tinea species (tinea corporis, tinea pedis, etc.).
• Onychomycosis caused by dermatophytes and/or yeast.
• Pityriasis versicolor.
• Vulvovaginal and oropharyngeal candidiasis.
Itraconazole has a broad spectrum of antifungal action, and is also widely used
to treat systemic fungal infections (e.g. aspergillosis, candidiasis, cryptococcosis
and histoplasmosis), deep mycoses (e.g. sporotrichosis, chromoblastomycosis,
paracoccidiodomycosis and histoplasmosis) and for prophylaxis of fungal
infection in patients with neutropenia and HIV.
It is effective in both a continuous and pulsed regimen for fungal nail
­infection. Candida onychomycosis responds very well to pulsed i­traconazole;
however, non-dermatophyte moulds causing onychomycosis (such as
­
­Scytalidium) do not respond. When treating onychomycosis with systemic
drugs, the causative organism should therefore be identified and host factors
such as c­ o-morbidities and concurrent medication carefully considered as well
as the extent and severity of disease.
Itraconazole also has antiangiogenic effects and inhibits hedgehog
signalling pathways, and is currently undergoing trials in various malignant
diseases.
++Formulations/Presentation
• 100 mg capsules.
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• Oral liquid (10 mg/mL) is suitable for children and HIV/immunosuppressed
patients with oral or oesophageal candidiasis.
• i/v infusion for systemic fungal infections.
++Dosages & suggested regimens
See Table 2. Itraconazole should be taken immediately after a meal to
maximize absorption. Absorption is impaired by any drug which reduces gastric
acidity. The treatment regimen and dosage vary according to indication. In the
treatment of fungal nail disease, improvement may be slow and full benefit
not apparent until after treatment has been completed.
TABLE 2 Indications and dosage regimens of itraconazole for skin disease
Indication
Dose
Vulvovaginal candidiasis
200 mg twice daily for 1 day
Pityriasis versicolor
200 mg once daily for 7 days
Tinea corporis, tinea cruris
100 mg once daily for 15 days or 200 mg
once daily for 7 days
Tinea pedis, tinea manuum
100 mg once daily for 30 days or 200 mg
twice daily for 7 days
3–5 mg/kg/d up to 200 mg daily for
2–6 weeks or pulsed regimen (see Use in
special situations – Children)
Tinea capitis in younger children
(unlicensed)
Oropharyngeal candidiasis
100 mg once daily for 15 days
Onychomycosis (dermatophyte or Candida)
200 mg once daily for 3 months or a
pulsed regimen of 200 mg twice daily for
7 days a month, i.e. subsequent courses
repeated ­after 21 day intervals. 2 pulses for
­fingernails, 3 pulses for toenails
++Baseline investigations & considerations
• Mycology should confirm a fungal infection before starting treatment for
suspected onychomycosis.
• LFTs in patients with history of liver disease.
• Pregnancy testing and ensure adequate contraception in females of
childbearing age.
++Monitoring
LFTs in patients with pre-existing liver disease, those taking continuous
­treatment over a month or if receiving other hepatotoxic drugs.
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++Contraindications & cautions
Contraindications:
• Hypersensitivity to itraconazole or related azoles.
• Acute porphyria.
• Pregnancy.
Use itraconazole only after careful consideration and with caution:
• Liver disease: use at reduced dosage if the benefit outweighs risk of
­hepatotoxicity. LFTs should be monitored.
• Cardiac failure: itraconazole has been associated with congestive cardiac
failure after high doses and long treatment courses. Caution is advised in
patients at high risk of heart failure, i.e. the elderly and those with cardiac
disease. Baseline echocardiography may be indicated.
++Important drug interactions
As itraconazole is mainly metabolized by CYP3A4, potent inhibitors of this
enzyme may increase its bioavailability. Examples are: ritonavir, indinavir,
clarithromycin and erythromycin. Likewise enzyme inducers including
rifampicin, may reduce bioavailability. Itraconazole may also inhibit the
metabolism of many other drugs metabolized by CYP450 3A4 and lead to an
increased risk of toxicity.
The following should not be given with itraconazole: mizolastine, cisapride,
triazolam, oral midazolam, dofetilide, quinidine, pimozide, statins metabolized
by CYP3A4 (atorvastatin, lovastatin and simvastatin)
Caution is advised with the following drugs:
• Calcium channel blockers due to pharmacological interactions and additive
negative inotropic effects which may precipitate cardiac failure.
• Cardiac glycosides (digoxin).
• Ciclosporin (cyclosporine), tacrolimus and sirolimus metabolism is inhibited.
Reduced dosage and monitoring of drug levels may be required.
• Coumarin anticoagulants: effect may be enhanced.
• Inhaled corticosteroids: metabolism may be impaired with long-term
­itraconazole leading to iatrogenic Cushing's syndrome.
• HIV protease inhibitors such as ritonavir, indinavir, saquinavir.
++Adverse effects & their management
• Gastrointestinal: nausea and abdominal pain are the most ­
common
side-effects and are generally mild. Side-effects are dose dependent
­
­therefore the dose can be reduced.
• Hepatitis: this is very uncommon (<1/10,000) but potentially serious. The risk
is increased in pre-existing liver disease, with prolonged therapy (>1 month)
and high dosage. Patients should be advised of the signs and symptoms of
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hepatitis (see below) and treatment stopped immediately. In most cases,
LFTs normalize after withdrawal of treatment.
• Dermatological: pruritus, acute generalized exanthematous ­
pustulosis,
urticaria, Stevens–Johnson syndrome and photoallergic reactions have
­
been reported. Adverse cutaneous reactions are more common in
­immunosuppressed patients.
• Cardiovascular: see Cautions
• Headache, dizziness, hypersensitivity reactions, thrombocytopenia and decreased libido can also occur.
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
Itraconazole is embryotoxic and teratogenic in animals and is contraindicated in
pregnancy except for life-threatening infections. Effective contraception must
be in place during treatment and until the next menstrual period following
treatment cessation. It may cause menstrual irregularities.
Lactation
Small amounts of itraconazole are excreted in human breast milk so should not
be taken during lactation.
Children
Itraconazole is unlicensed in children under the age of 12 years but it has been
proven to be safe, effective and well-tolerated. It is commonly prescribed
for tinea capitis due to Trichophyton species. Its efficacy is comparable
to griseofulvin and terbinafine, with high complete cure rates when given
for 2–3 weeks. Itraconazole is superior to terbinafine for the treatment of
Microsporum species, but griseofulvin remains the treatment of choice in many
countries due to its lower cost. The duration of treatment is 2–6 weeks and
dosage is based on weight and formulation, up to a maximum of 200 mg daily.
The dose for capsules is 5 mg/kg/d and for oral solution is 3 mg/kg/d.
For tinea capitis treatment can be given continuously for 2–6 weeks or as a
pulsed regimen of 1 week itraconazole then 2 weeks off between each pulse,
for up to 3 pulses in total. The schedule for pulsed treatment for onychomycosis
is the same as in adults with a dose of 5 mg/kg.
Elderly
Care should be taken in those at risk of cardiac failure, and taking drugs which
may interact with itraconazole. The prevalence of onychomycosis in the elderly
is high but generally morbidity is low; therefore, the risks/benefits of treating
onychomycosis with any oral antifungal should be carefully considered before
embarking on potentially lengthy courses of treatment.
Special point
In addition to antifungal properties, itraconazole inhibits the hedgehog
signalling pathway, similar to vismodegib (see Vismodegib). This may account
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for the drug's teratogenic effects. Itraconazole shows activity against basal cell
carcinoma in humans and may have therapeutic potential in oncology.
++Essential patient information
Females of childbearing age should avoid pregnancy and use effective
contraception.
Patients should be informed of the signs and symptoms of liver dysfunction,
e.g. anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine, and
­advised to discontinue treatment and seek medical advice if affected.
Fluconazole
Fluconazole is very well absorbed after oral administration and does not
undergo first pass metabolism, so serum concentrations are identical whether
administered orally or parentally. Unlike itraconazole, it is highly water soluble
and absorption is not affected by food intake or gastric acidity. It is distributed
widely throughout the body and appears to be eliminated from the skin more
slowly than from the plasma. Most of the drug is excreted unchanged in the
urine.
++Indications & dermatological uses
• Genital candidiasis, oropharyngeal candidiasis.
• Systemic candidiasis including candidaemia and disseminated candidiasis.
• Superficial mycoses: tinea pedis, tinea corporis, tinea cruris, pityriasis
­versicolor and dermal candidiasis.
Other uses include:
• Tinea capitis in children (off label).
• Recalcitrant toenail onychomycosis (off label).
• Prophylaxis or treatment of systemic mycoses such as cryptococcosis and
­candidosis in HIV infection, treatment of histoplasmosis and cocciodomycosis and prevention of fungal infections in immunocompromised patients.
++Formulations/Presentation
• 50 mg, 150 mg and 200 mg capsules; a 150 mg single capsule pack is available for sale to the public for the treatment of vaginal candidiasis.
• Oral suspension: 50 mg/5 mL, 35 mL oral suspension, 200 mg/5 mL, 35 mL
oral suspension.
• i/v infusion.
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++Dosages & suggested regimens
• Genital candidiasis: 150 mg as single oral dose.
• Oropharyngeal/oesophageal candidiasis: 50 mg daily (100 mg maximum
daily in recalcitrant infection) given for 7–14 days.
• Chronic atrophic candidiasis associated with dentures: 50 mg daily for
14 days.
• Oesophageal and mucocutaneous candidiasis: 50 mg for 14–30 days. In
­unusually difficult cases of mucosal candidal infections the dose may be
­increased to 100 mg daily.
• Tinea pedis, tinea corporis, tinea cruris, pityriasis versicolor and dermal
­candidiasis: 50 mg daily for 2–4 weeks (up to 6 weeks in tinea pedis).
Other reported regimens (unlicensed) include pulse dosing of 150 mg
fluconazole once weekly for tinea corporis and tinea cruris, and 300 mg once
weekly for 6–9 months for onychomycosis. However, fluconazole is not licensed
for the treatment of nail disease and has lower efficacy than other licensed
drugs, so should only be considered when these are contraindicated or not
tolerated.
Special point
Resistant strains of Candida may emerge during prolonged treatment with
fluconazole. C. krusei, C. glabrata and certain strains of C. albicans are also
primarily resistant to this drug.
++Baseline investigations & considerations/Monitoring
• Baseline/pre-therapy: FBC (CBC), renal function and LFTs in those with underlying illnesses. Pregnancy test.
• During therapy: repeat LFTs after 6 weeks of treatment.
++Contraindications
• Fluconazole should not be used in patients with known hypersensitivity to
it or related azoles.
• Pregnancy.
++Cautions
Dose reduction required in renal impairment as fluconazole is mostly excreted
unchanged by the kidneys.
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++Important drug interactions
• Fluconazole may inhibit both the 3A4 and 2C9 isoforms of CYP450.
• Rifampicin: modest reduction in fluconazole levels due to CYP450 induction
by rifampicin.
• Phenytoin: levels may be increased, so monitoring required.
• Ciclosporin: levels may be increased so monitoring required.
• Hydrochlorothiazide may increase levels of fluconazole.
++Adverse effects & their management
The adverse effect profile of fluconazole is similar to itraconazole (see above)
but fluconazole is less frequently associated with hepatotoxicity. Adverse
events usually occur with treatment duration of over 1 week but most are
reversible when the drug is discontinued.
++Use in special situations
Pregnancy (FDA Category C)
Fluconazole is contraindicated in pregnancy as it has been associated with
birth defects in the children born to mothers taking high dose long-term
treatment. Pregnancy should be excluded before starting therapy and females
of childbearing age should use adequate contraception.
Lactation
Fluconazole is excreted in breast milk at similar levels to plasma, and should
not be used during lactation.
Children
Fluconazole is licensed for use in children, including neonates in the treatment
of mucosal candidiasis, invasive candidal infections and cryptococcal infections,
but not for superficial skin infection. Clearance is faster than in adults so higher
doses are needed (up to 12 mg/kg/d for severe infection. Fluconazole has been
reported to be effective in childhood tinea capitis at doses of 6 mg/kg/day for
3–6 weeks with comparable efficacy to griseofulvin and the advantage of a
shorter treatment duration.
Ketoconazole
Ketoconazole was the first broad-spectrum imidazole for oral use in the
treatment of systemic mycoses. However, in 2013 the European Medicines
Association (EMA) issued advice against the use of oral ketoconazole for
treatment of fungal infections due to the risk of severe liver damage and
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availability of safer alternatives. Ketoconazole hepatotoxicity ranges from
asymptomatic transient raised transaminases and alkaline phosphatase to
severe derangement and death. Females over the age of 40 years on long-term
therapy appear at highest risk. Liver damage may progress despite immediate
drug withdrawal. Although the estimated incidence of severe hepatotoxicity
is less than 1 in 10,000, in view of this serious hazard and availability of safer
drugs, the EMA advises that its use is no longer justified.
Ketoconazole was previously licensed for use in candidiasis, dermatophytosis
and malassezia folliculitis at doses of 200–400 mg daily. Topical ketoconazole
is still available in cream and shampoo formulations for the treatment of
seborrhoeic dermatitis and pityriasis versicolor.
Terbinafine
++Classification & mode of action
Terbinafine is a synthetic allylamine which is highly effective against a broad
spectrum of dermatophyte infections. It inhibits the biosynthesis of fungal
­ergosterol at the point of squalene epoxidase. This leads to accumulation of
the intermediate squalene, which appears to be fungicidal, and deficiency
of the end product ergosterol, which is fungistatic. Ergosterol is an integral
component of fungal cell membranes and squalene is thought to interfere with
fungal membrane function and cell wall synthesis. Although the biosynthesis of
cholesterol relies on the activity of squalene epoxidase, terbinafine has a much
lower binding affinity for the mammalian enzyme and therefore demonstrates
selective toxicity to fungal systems.
Terbinafine is well absorbed after oral dosage (especially after a high fat
meal/with acidic food) and reaches peak plasma concentrations within about
2 hours. Primary metabolism occurs in the liver and involves at least seven
CYP450 enzymes. Inactive metabolites are slowly eliminated, mainly in the
urine. The polyfunctional nature of terbinafine as a substrate reduces potential
drug interactions. Terbinafine inhibits CYP2D6, and the activity of this enzyme
may not return to normal for months following cessation of a prolonged
course of treatment.
Terbinafine is preferentially taken up into fat, and reaches high
concentrations in the sebum, skin and nails. It is delivered to the stratum
corneum primarily by sebum and to a lesser extent by diffusion through the
dermoepidermis. During the first 2 weeks of therapy, concentrations within the
stratum corneum increase to 75 times greater than plasma concentrations. It is
also incorporated into the hair matrix. The long terminal half-life of 200–400
hours may reflect its slow elimination from tissues such as skin and adipose.
The clinical efficacy of terbinafine is related to high drug levels at the site of
infection and sustained fungicidal activity following discontinuation of therapy.
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++Indications & dermatological uses
The licensed indications of terbinafine are dermatophyte infections of the skin
and nails where oral therapy is appropriate (site, severity, etc.).
Terbinafine is the most active antidermatophyte agent. It is the treatment
of choice for dermatophyte onychomycosis, with superior long-term results in
toenail disease than griseofulvin, ketoconazole, fluconazole and itraconazole.
Clinical trials have shown greater or equal efficacy compared with other
antifungals, with the benefit of a shorter treatment period. It is also highly
effective in treating chronic dermatophyte infections on the hands, feet and
body.
Terbinafine is also an effective treatment for tinea capitis, though not
yet licensed in the UK for treating children. It is however, licensed for this
complaint in the USA and parts of Europe. The commonest causative agents
for tinea capitis vary from one part of the world to another. In urban settings
in Europe and the USA, the main dermatophyte fungi causing tinea capitis
are Trichophyton species, which cause an endothrix pattern of infection where
arthrospores are most abundant within the hair shaft (see Figure 2).
Arthrospores
Ectothrix
Endothrix
Hair cortex
Fungal hyphae
FIGURE 2 Different arthrospore distribution in ectothrix and endothrix fungal hair
infection.
Systemic terbinafine is usually ineffective at treating superficial yeast
infections such as candidosis and pityriasis versicolor.
++Formulations/Presentation
• Scored tablets containing terbinafine hydrochloride equivalent to 250 mg
terbinafine.
• Oral granules that can be sprinkled on food have been approved by the USA
FDA for use in children aged 4 years or over.
• Topical formulation (terbinafine hydrochloride 1%, 5%) cream.
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++Dosages & suggested regimens
The usual adult dose is 250 mg once daily. The duration of treatment depends
on the site and severity of the infection. It is usually 2–6 weeks in tinea pedis,
2–4 weeks in tinea cruris, 4 weeks in tinea corporis, 6 weeks–3 months in nail
infections (occasionally longer in toenail infections). Additional topical or
surgical treatment to infected nails may improve cure rates. The maximum
clinical effect in nail infections may not be seen for several months after
cessation of treatment until the healthy nail has grown.
Although unlicensed in children in the UK, studies have confirmed good
cure rates in tinea capitis.
• Child over 1 year, bodyweight 10–20 kg: 62.5 mg once daily.
• Child bodyweight 20–40 kg: 125 mg once daily.
• Child bodyweight over 40 kg: 250 mg once daily.
The duration of treatment for tinea capitis depends on the causative organism.
Trichophyton species show good response rates within 4 weeks of treatment.
Microsporum infection requires prolonged therapy of 6 weeks or more. The
difference in clinical response may be related to the ectothrix infection pattern
of Microsporum spp. as opposed to the endothrix pattern associated with the
genus Trichophyton, with a consequent decreased accessibility of antimycotics
to the fungal spores on the surface of the hair shaft in the former.
Treatment of onychomycosis in patients with HIV infection may require
higher dose therapy, e.g. 500 mg daily. Additional use of a topical antifungal
preparation and avulsion of diseased nail may improve cure rates in severe
toenail onychomycosis.
++Baseline investigations & considerations
Mycological confirmation of infection and causative organism should ideally
be obtained before starting treatment, especially when prolonged treatment
is likely (onychomycosis).
++Monitoring
It is now recommended to check LFTs at baseline, then every 4–6 weeks during
treatment.
++Contraindications
• Terbinafine hypersensitivity.
• Severe renal or liver impairment.
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++Cautions
• Psoriasis: exacerbation has been reported very rarely with terbinafine.
• Systemic and cutaneous lupus erythematosus may be exacerbated or­
induced.
• Hepatic impairment: hepatic clearance of terbinafine is reduced in liver
­disease and as it may also cause hepatotoxicity, its use should be avoided
in liver disease.
• Renal impairment: reduce dosage by half if estimated glomerular fi
­ ltration
rate (eGFR) is less than 50 mL/min/1.73 m2 and no suitable alternative is
­available.
++Important drug interactions
• CYP450 enzyme inducers (e.g. rifampicin) and inhibitors (e.g. cimetidine)
may accelerate or reduce terbinafine metabolism respectively, and its dosage may need adjustment.
• CYP2D6 mediated drug metabolism is inhibited by terbinafine. Patients taking drugs metabolized by this enzyme (β-blockers, SSRIs, MAOIs type B) may
require closer monitoring.
• Oral contraceptive metabolism in not usually affected but there have been
sporadic reports of menstrual disturbances/breakthrough bleeding.
• Warfarin: rare cases of increased or decreased prothrombin time have been
reported so closer monitoring is indicated.
++Adverse effects & their management
• Mild gastrointestinal effects including abdominal discomfort, anorexia,
nausea and diarrhoea are common (>2%). They may settle with continued
treatment. Loss of taste/a metallic taste is not uncommon and although
­usually reversible, permanent taste loss has been reported.
• Dermatological: include pruritus, urticaria, hair loss, p
­ hotosensitivity, induction or exacerbation of subacute cutaneous or ­systemic ­lupus erythematosus, exacerbation of psoriasis and serious c­ utaneous ­adverse ­reactions
(acute generalized exanthematous pustulosis, Stevens–Johnson syndrome
and toxic epidermal necrolysis). Treatment should be discontinued immediately if a progressive rash develops.
• Hepatotoxicity is very rare. It may present with hepatitis or cholestasis.
Treatment should be discontinued immediately if signs of liver dysfunction
develop.
• Other non-specific: include headache, flu-like ­symptoms, o
­ ccasionally with
arthralgia or myalgia.
• Psychiatric: have been reported very rarely.
• Blood disorders (including leukopenia and t­hrombocytopenia) have been
reported very rarely.
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++Use in special situations
Pregnancy & pre-conception (FDA Category B)
Although there is no evidence of harm, the use of terbinafine is not
recommended in pregnancy unless potential benefit outweighs risk.
Lactation
Avoid as terbinafine is excreted in milk and the ratio of this drug in milk to
plasma after oral administration is 7:1.
Children
Although not licensed for use in children in the UK, terbinafine has been shown
to be well-tolerated and effective. The drug may have a higher clearance and
shorter half-life in this age group. It has recently been licensed by the FDA for
use in children from the age of 4 years in the USA. For dosages in tinea capitis,
see page 68.
++Essential patient information
Patients should be advised to seek prompt medical attention if they develop
a new or worsening rash or signs and symptoms of liver dysfunction (e.g.
jaundice, right upper abdominal pain, nausea, fatigue, vomiting, dark urine or
pale stools). They should be advised to report any signs of taste disturbance,
smell disturbance and or depressive symptoms.
Griseofulvin
++Classification & mode of action
Griseofulvin was first obtained from the mould Penicillium griseofulvum in
1939 and has been used as an oral therapy for superficial fungal infection since
the 1960s. It has fungistatic actions and is most effective against dermatophytes
that cause tinea (ringworm) infections. It is deposited in newly formed keratin
in the skin and hair and is thought to confer resistance against fungal infection
by inhibiting the formation of fungal microtubules. Griseofulvin may also have
anti-inflammatory and immunomodulatory effects.
GI absorption varies considerably between individuals, mainly because the
drug is insoluble in the upper GI tract. Peak serum levels are usually found
about 4 hours after ingestion, and higher blood levels can usually be attained
if ­griseofulvin is taken after a fatty meal. Absorption is also improved by a
­reduction in particle size. It is metabolized in the liver and excreted in the
urine, faeces and in sweat.
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The duration of treatment depends on the length of time required for the
infected keratin to be shed, which may be several months. Effective delivery to
the skin depends upon eccrine sweating, and can be impaired in disease where
the sweat ducts are obstructed.
++Indications & dermatological uses
• Superficial dermatophye infections (nail, skin, hair) where topical therapy
has failed or is inappropriate (severe or widespread disease).
Griseofulvin has specific activity against dermatophytes. It is a long-­established
treatment for infections of the scalp and nails and has been used safely in
children for many years, being available as both tablet and suspension
preparations. However, it has a bitter taste and prolonged treatment may
be required. For nail infection, newer more effective antifungal drugs are
preferred. Griseofulvin is licensed to treat tinea capitis in children, and is still
widely used in this context, but newer drugs (itraconazole and terbinafine)
appear to be equally effective with shorter treatment durations. Griseofulvin is
not effective against Candida, Pityrosporum, Scopulariopsis or Scytalidium spp.
• There have been anecdotal reports of benefit from griseofulvin treatment
in a range of dermatological conditions including lichen planus and eosinophilic fasciitis, and recent research has highlighted a potential antitumour
effect.
++Formulations/Presentation
• Microsize tablets containing 125 mg and 500 mg griseofulvin.
• Ultramicrosize tablets containing 125 mg and 250 mg griseofulvin.
• A peppermint flavoured oral suspension containing 125 mg/5mL griseofulvin
is useful for treating children.
++Dosages & suggested regimens
The usual adult dose (microsize preparation) is 500 mg/d in a single or divided
dose taken after meals. Where the ultramicrosize preparation is available, the
dose is 375 mg/d. For children, see Use in special situations.
++Baseline investigations & considerations
No routine investigations are needed for short courses (up to 6 weeks).
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++Monitoring
During therapy: FBC and LFTs after 3 months.
++Contraindications
• Hypersensitivity to griseofulvin or any component of the formulation.
• Severe liver disease.
• Porphyrias, particularly acute intermittent; also best avoided in variegate
and porphyria cutanea tarda.
• Systemic lupus erythematosus (SLE).
• Pregnancy.
++Cautions
• Hepatic impairment.
• Penicillin allergy: hypersensitivity cross-reaction between penicillins and
­griseofulvin is possible.
• Photosensivity: avoid exposure to intense sunlight to prevent p
­ hotosensitivity
reactions.
++Important drug interactions
• Griseofulvin may decrease the blood level of drugs metabolized by CYP3A4
and adjustment of their dosage may be required.
• Coumarin anticoagulant activity (warfarin) is decreased so closer monitoring is required.
• Oral contraception: metabolism is increased and contraceptive failure may
occur, so additional precautions are required during griseofulvin treatment
and for 1 month afterwards.
• Ciclosporin: serum levels are decreased by griseofulvin.
++Adverse effects & their management
The most common side-effects of griseofulvin are listed below. Serious reactions
are extremely rare.
• Headache: is a common adverse reaction and is due to a reduction in
­vascular tone. It usually improves with continued treatment. Nausea, diarrhoea and vomiting are frequent side-effects. These may be helped by dividing the dose.
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• Dermatological: are rare and include urticaria, ­
photosensitivity,
erythema
multiforme
and
toxic
epidermal
necrolysis.
A dermatophytide (id or ‘ide’) allergic reaction is occasionally seen after
starting oral antifungal medication including griseofulvin. This usually presents with widespread follicular papules, especially on the face and may be
mistaken for a drug rash.
• Neuropsychiatric: have been reported including confusion, ­drowsiness, impaired concentration and peripheral neuropathy. The sedative ­effects of
alcohol may be enhanced.
• SLE: may be exacerbated or precipitated.
• Alcohol: toxic effects are enhanced by griseofulvin and alcohol ingestion
may precipitate a disulfiram-like reaction.
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
Griseofulvin disrupts the mitotic spindle and is capable of inducing aneuploidy
(abnormal segregation of chromosomes following cell division) and causing
­embryo toxicity. Rare cases of conjoined twins have been reported following
griseofulvin therapy in early pregnancy. Females should not take the drug
during pregnancy or become pregnant within 1 month of stopping treatment.
Men should not father children within 6 months of treatment.
Lactation
Griseofulvin should be avoided in lactation as its safety is not established.
Children
Griseofulvin is the only licensed treatment for treatment of superficial fungal
infections including tinea capitis in children under the age of 12 years. In
children, the recommended dose is 10 mg/kg/d (maximum 500 mg daily). The
duration of treatment varies from 2 to 4 weeks in tinea corporis and 2–4 months
in tinea ungueum. The recommended duration of griseofulvin treatment for
tinea capitis is 6–12 weeks. To avoid treatment failure, however, the dosage
may need to be increased to 20 mg/kg/d (maximum 1 g daily) for the same
­period of time. This is particularly advisable in patients with endothrix infection
(see Table 3).
Griseofulvin is ineffective in at least one-third of children with tinea
capitis, most likely due to inadequate dosing, poor adherence and insufficient
treatment duration. Adjunctive therapy with an antifungal shampoo
(ketoconazole or selenium sulphide) is recommended for the first 2 weeks
to minimize transmission to others. Prolonged treatment is required to clear
kerion (12–16 weeks) but the routine additional use of systemic corticosteroids
confers no benefit and is not recommended.
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TABLE 3 Oral antifungal agents for tinea capitis in children
*
Agent
Dosage
Griseofulvin*
10–20 mg/kg/d for 6–12 weeks
Terbinafine (for Trichophyton tonsurans)
<20 kg: 62.5 mg/kg
20–40 kg: 125 mg/kg
>40 kg: 250 mg – all daily for 1 month
Itraconazole
3–5 mg/kg/d (max 100 mg/d) for 2–6
weeks
Or weekly pulses of 5 mg/kg/d every 4
weeks for 2–3 months
Fluconazole
3–6 mg/kg/d for 3–6 weeks
Licensed in the UK for treatment of tinea capitis in children.
Children with tinea capitis on treatment may continue to shed fungal
spores for several months and do not need to be excluded from school.
Children in contact with tinea capitis should be examined very carefully for
signs of infection (which may be as little as a few broken hairs) and given oral
antifungals if infection is confirmed. Asymptomatic carriers do not routinely
need oral antifungals but should be given an antifungal shampoo at least
twice weekly.
++Essential patient information
• Adults should be advised to avoid alcohol.
• Adults should avoid driving or operating machinery if affected by d
­ rowsiness.
• Adults should be advised about contraceptive and family planning
­precautions and the reduced effectiveness of oral contraceptives.
With acknowledgements to Wanda Robles, author of this chapter in the 1st
edition.
++Further reading
Azoles
Finch JJ, Warchaw EM. Toenail onychomycosis: current and future treatment
options. Dermatol Therapy 2007;20(1):31–46.
Fuller LC, Barton RC, Mohd Mustapa MF, Proudfoot LE, Punjabi SP, Higgins EM.
British Association of Dermatologists guidelines for the management of tinea
capitis 2014. Br J Dermatol 2014;171(3):454–63.
Gonzalez U, Seaton T, Bergus G, Jacobson J, Martinez-Monzon C. Systemic
antifungal therapy for tinea capitis in children. Cochrane Database Syst Rev
2007;4:CD004685.
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Antifungals
Gupta AK, Katz HI, Shear NH. Drug interactions with itraconazole, fluconazole,
and terbinafine and their management. J Am Acad Dermatol 1999;41:237–48.
Kakourou T, Uksal U. European Society for Pediatric Dermatology. Guidelines for
the management of tinea capitis in children. Pediatr Dermatol 2010;27(3):226–8.
Terbinafine
Ahmen M, Lear JT, Madan V, Mohd Mustapha MF, Richardson M. British
Association of Dermatologists guidelines for the management of onychomycosis.
Br J Dermatol 2014;171:937–58.
Bell-Syer SE, Khan SM, Torgerson DJ. Oral treatments for fungal skin infections
of the foot. (Review). Cochrane Database Syst Rev 2012;10:CD003584. doi:
10.1002/14651858.CD003584.pub2. Review.
Cribier BJ, Paul C. Long-term efficacy of antifungals in toenail onychomycosis:
a critical review. Br J Dermatol 2001;145:446–52.
Elewski BE. Tinea capitis: a current perspective. J Am Acad Dermatol 2000;
42:1–20.
Roberts DT, Taylor WD, Boyle J. Guidelines for treatment of onychomycosis.
Br J Dermatol 2003;148:402–10.
Griseofulvin
Fuller LC, Barton RC, Mohd Mustapa MF, Proudfoot LE, Punjabi SP, Higgins EM.
British Association of Dermatologists guidelines for the management of tinea
capitis 2014. Br J Dermatol 2014;171(3):454–63.
Grover C, Arora P, Manchanda V. Comparative evaluation of griseofulvin,
terbinafine and fluconazole. Int J Dermatol 2012;51:455–8.
Kakourou T, Uksal U. European Society for Pediatric Dermatology. Guidelines
for the management of tinea capitis in children. Pediatr Dermatol 2010;
27:226–8.
Moriarty B, Hay R, Morris-Jones R. The diagnosis and management of tinea.
(Clinical Review) BMJ 2012;435:37–42.
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Antihistamines
Tabi A. Leslie & Clive E. Grattan
Systemic antihistamines are commonly prescribed to relieve the symptoms
of itch (pruritus). They are widely used in many dermatological conditions
associated with itch including urticaria, pruritic dermatoses such as eczema,
chronic pruritus, insect bites and stings. Antihistamines are also useful in
treating patients with allergic drug reactions and as an adjunct to adrenaline
(epinephrine) in the emergency treatment of anaphylaxis and histaminergic
angioedema.
This chapter mainly describes the use of H1 antagonists in dermatology.
There is a short section on the dermatological uses of H2 antagonists and
doxepin, which has both H1 and H2 antagonist effects.
++Classification & mode of action
H1 antihistamines are classified as first generation, which are sedating; (these
include chlorpheniramine, diphenhydramine, promethazine and hydroxyzine)
and newer antihistamines which are relatively non-sedating, and include
loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, acrivastine,
bilastine, ebastine, mizolastine and rupatadine (see Table 1).
Acting on H1 receptors in the skin, histamine induces vasodilation,
increased vascular permeability, itching and smooth muscle contraction as
well as in the respiratory and gastrointestinal (GI) tracts. All H1 antihistamines
reversibly act on H1 receptors as inverse agonists. Some of the sedating (firstgeneration) antihistamines have additional antimuscarinic, antiadrenergic,
antiserotonergic antagonizing or local anaesthetic effects.
H1 antihistamines are generally well-absorbed after oral administration. The
time course of action is variable, although symptomatic relief usually begins
within 15–30 minutes, lasts for 1–2 hours and in some cases lasts for 12–24
hours or longer. It is usually maximal within 1–2 hours and continues for 3–6
hours or longer.
Cetirizine, levocetirizine, loratadine, desloratadine and mizolastine have
a slower onset and prolonged duration of action, peak blood levels from 45
minutes and lasting for at least 24 hours. Therefore, they are effective when
given once as a daily dosage.
Most H1 antihistamines are extensively metabolized in the liver by
cytochrome P450 (CYP450) enzymes (particularly CYP2D6 and CYP3A4) except
cetirizine, levocetirizine, fexofenadine and, to a lesser extent, mizolastine.
Some antihistamines have active H1 antihistamine metabolites. Desloratadine
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and cetirizine are the active metabolites of loratadine and hydroxyzine,
respectively. Some H1 antihistamines and their metabolites are eliminated
predominantly by renal mechanisms (acrivastine, cetirizine and levocetirizine,
an isomer of cetirizine). These antihistamines, including mizolastine and
rupatadine, cause less sedation and psychomotor impairment than the older
antihistamines because they penetrate the blood–brain barrier only to the
slight extent.
Prolonged use of H1 antihistamines may lead to some reduction in
effectiveness, although tolerance of sedative effects of classical antihistamines
is much more common than tachyphylaxis of antihistamine effects.
++Indications & dermatological uses
• The licensed indications of most antihistamines include urticaria with or
without angioedema. Second-generation (non-sedative) antihistamines are
the drugs of choice for daytime symptoms. First-generation antihistamines
may be useful to relieve symptoms at night because of their sedating properties, but they are not recommended during the day.
• Sedating antihistamines may be useful in the treatment of pruritus caused
by other dermatological conditions such as atopic eczema. Hydroxyzine is
approved for use in pruritus caused by contact or atopic dermatitis.
• H1 antihistamines are also used for type I hypersensitivity reactions including anaphylaxis. Most are approved for allergic rhinoconjunctivitis. Chlorphenamine and promethazine are approved for use in anaphylaxis.
• Some antihistamines have antiemetic properties, such as diphenhydramine
and promethazine. These may be used in motion sickness, Ménière's disease
and other vestibular disorders. Diphenhydramine is available as a standard over-the-counter night-time sleep aid in the UK and is widely used for
urticaria in the USA.
++Formulations/Presentation
The generic names and dosages of oral antihistamine tablets in the UK are
listed in Table 1.
The following are available in solution or syrup form: cetirizine,
chlorpheniramine,
clemastine,
cyproheptadine,
diphenhydramine,
desloratadine and promethazine.
Some drugs can be given parenterally, but this frequently causes local
irritation. Chlorphenamine can be given i/v or i/m at a dose in adults of 10 mg,
repeated if required with a maximum of four doses in 24 hours. Parenteral
use is usually reserved for anaphylaxis, or if there is difficulty swallowing in
patients with angioedema.
Some topical antihistamines are available but prolonged use should be
avoided because of a relatively high risk of contact sensitization.
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TABLE 1 Generic names and dosages and suggested regimens of antihistamines
used in dermatology in the UK
Generic name
Oral dose (adult and
child 12–18 y)
Oral dose (child under 12 y)
Non- or low-sedating antihistamines
Acrivastine
8 mg tds
Unlicensed
Bilastine
20 mg od
Unlicensed
Cetirizine
10 mg od
1–2 y: 250 μg/kg bd
2–6 y: 2.5 mg bd
6–12 y: 5 mg bd
Desloratadine
5 mg od
1–6 y: 1.25 mg od
6–12 y: 2.5 mg od
Fexofenadine
180 mg od
Unlicensed
Loratadine
10 mg od
2–12 y, <30 kg: 5 mg od
2–12 y, >30 kg: 10 mg od
Mizolastine
10 mg od
Unlicensed
Rupatadine
10 mg od
Unlicensed
Sedating antihistamines
Alimemazine
10 mg bd/tds
(max. 100 mg/d)
Elderly: 10 mg od/bd
2–5 y: 2.5 mg tds/qds
5–12 y: 5 mg tds/qds
Chlorphenamine
4 mg 4–6 hourly
(max. 24 mg/d)
Elderly: max. 12 mg/d
1–24 mo: 1 mg bd
2–6 y: 1 mg 4–6 hourly (max. 6
mg/d)
6–12 y: 2 mg 4–6 hourly (max. 12
mg/d)
Diphenhydramine
25–50 mg 4–6 hourly
(max 24 mg/d)
6.25–25 mg tds/qds (max 5 mg/kg or
300 mg daily)
Hydroxyzine
25 mg nocte
(up to 25 mg tds/qds if
required)
6 mo–6 y: 5–15 mg nocte (up to 50
mg tds/qds)
6–12 y: 15–25 mg nocte (up to
50–100 mg daily tds/qds)
Promethazine
10– 20 mg tds/qds
2–5 y: 5 mg bd (or 5–15 mg nocte)
5–10 y: 5–10 mg bd (or 10–25 mg
nocte)
>10 y: 10–20 mg bd (or 25 mg nocte,
up to 25 mg bd if required)
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++Dosages & suggested regimens
Antihistamines are usually given orally. Standard doses for their administration
in urticaria with or without angioedema are given in Table 1. The recommended
first-line treatment is with non-sedating second-generation H1 antihistamines.
If standard dosing is not effective in chronic urticaria, increasing the dosage up
to fourfold is recommended. For patients who do not respond to a fourfold
increase in dosage second-line therapies should be added to the antihistamine.
Treatment options include montelukast 10 mg daily, omalizumab 300 mg by s/c
injection every 4 weeks or immunosupressant drugs, e.g. ciclosporin.
++Baseline investigations & considerations
No routine monitoring is required.
++Contraindications & cautions
• Mizolastine is partly metabolized by CYP3A4. Increased levels of this drug
may predispose to serious cardiovascular adverse effects (see below) so it
should not be given at doses greater than those recommended. It should
not be given to patients in whom there may be impaired drug metabolism,
such as those with liver disease, the elderly or those taking drugs that inhibit
CYP450 (see Important drug interactions). Patients should be instructed not
to drink grapefruit juice, which inhibits CYP450. Patients with cardiac disease may be at increased risk of cardiac adverse effects, and this drug should
not be given to patients with a bradycardia, QT prolongation, arrhythmias
or electrolyte imbalance.
• Antihistamines with substantial antimuscarinic (anticholinergic) activity
(mainly first-generation/sedating) should be used with caution or avoided
in patients with narrow-angle glaucoma or increased intraocular pressure,
prostatic hypertrophy, bladder neck obstruction, stenosing peptic ulcer, pyloroduodenal obstruction, asthma and chronic obstructive airways disease,
hyperthyroidism, cardiovascular disease and hypertension. Caution should
be applied to the elderly who may be more susceptible to side-effects.
• Acute intermittent porphyria may be precipitated by certain antihistermines. Chlorphenamine, desloratadine, loratadine and fexofenadine are
considered safe. Severe liver disease: avoid sedating antihistamines as they
increase the risk of coma.
• Severe renal impairment: reduced dosage or frequency of doing may be
required.
• Seizure disorders: use non-sedating antihistamines in preference.
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++Important drug interactions
• Mizolastine should not be given with drugs that can inhibit CYP450, as
these may increase its plasma levels and predispose to cardiac toxicity. These
include: azole derivatives such as antifungals, macrolides (clarithromycin,
erythromycin). Grapefruit juice also inhibits CYP450 and should be avoided. Mizolastine should not be given with drugs that may prolong the QT
interval, such as class IA and III antiarrhythmic agents (quinine, quinidine,
sotalol, amiodarone or halofantrine), antipsychotic drugs (haloperidol or
thioridazine) or doxepin.
• Central nervous system (CNS) depressants, such as barbiturates, anxiolytics,
opioid analgesics and alcohol, may have additive CNS depressive effects to
those of the sedating antihistamines.
• Monoamine oxidase inhibitors, used less frequently than in the past, are
contraindicated with chlorphenamine as they may prolong and intensify the
anticholinergic and sedative effects. Although widely cited as a potential interaction with other antihistamines, with the exception of cyproheptadine,
this has not been confirmed clinically.
• The vasopressor effect of epinephrine may be blocked and reversed by phenothiazine-type antihistamines (promethazine).
++Adverse effects & their management
Serious toxicity rarely occurs.
• Sedation occurs predominantly with first-generation antihistamines
because they are highly lipid-soluble and cross the blood–brain barrier readily, blocking central as well as peripheral H1 receptors. However, sedation and impaired performance may also occur with
second-generation drugs, so these cannot be considered universally nonsedating. A significantly lower incidence of sedation has been reported
with fexofenadine and loratadine compared with cetirizine and acrivastine.
Headache, dizziness, lassitude, sleep disturbances, abnormal co-ordination
and muscular weakness may also occur. In some patients effects disappear
spontaneously after 2–3 days. All patients, particularly those who perform
potentially hazardous tasks such as driving motor vehicles or operating
machinery, MUST be warned of these effects. Sedative effects may also be
potentiated by other CNS depressants, such as sedatives, anxiolytics and alcohol.
• Paradoxical stimulation (excitement) also occurs predominantly with firstgeneration antihistamines. Restlessness, insomnia, tremors, euphoria, nervousness, delirium and seizures may occur, particularly in children.
• Cardiovascular adverse effects are uncommon, and are usually limited to
overdose situations, or where elevated drug plasma concentrations have
occurred as a result of drug interactions, impaired liver function or old age.
With most antihistamines, adverse cardiac effects are due to anticholinergenic or quinidine-like effects, and include tachycardia, palpitation, widen80
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•
•
•
•
ing of the QRS complex and arrhythmias. Hypertension and hypotension
may occur. Mizolastine, rupatadine and bilastine may have the potential
to prolong the QT interval and, therefore, should be used with caution in
patients with cardiac disease.
Gastrointestinal adverse effects include epigastric pain, anorexia, nausea,
vomiting, diarrhoea and constipation. Administering the drug with meals or
with milk can decrease symptoms. Cholestasis, hepatitis and jaundice have
been reported rarely. Increased appetite and weight gain may occur with
cyproheptadine and mizolastine.
Hypersensitivity reactions: prolonged topical use of antihistamines should
be avoided because of the risk of developing allergic contact dermatitis.
Dermatitis can recur following subsequent topical or systemic exposure
to the drug or to a chemically related drug such as a local anaesthetic.
Photoallergic dermatitis has also been reported. Immediate-type hypersensitivity reactions to oral antihistamines have been reported rarely, and include urticaria, angioedema, and bronchospasm .
Anticholinergic effects occur predominantly with first-generation antihistamines, and include dryness of the mouth, nose and throat, dysuria, urinary retention, impotence, gastric reflux, constipation, vertigo, visual disturbance, blurred vision, diplopia, tinnitus, acute labyrinthitis, insomnia,
tremor, nervousness, irritability and facial dyskensia. In addition, tightening
of the chest, thickening of bronchial secretion, wheezing, nasal stuffiness,
sweating, chills, early menses, toxic psychoses, headache, faintness and paraesthesias have occurred at above-licensed doses.
Haematological adverse effects are rare and include agranulocytosis,
haemolytic anaemia, leukopenia, thrombocytopenia and pancytopenia.
++Use in special situations
Pregnancy/Lactation
The manufacturers of antihistamines advise avoidance of their use during
pregnancy. There is no evidence of teratogenicity, apart from for hydroxyzine
(FDA Category C), which has been associated with toxicity when given in high
doses in animal studies.
Other first-generation antihistamines are considered generally safe to use
during pregnancy. While no antihistamine can be considered entirely safe in
pregnancy, if one is required, chlorphenamine (FDA Category B) may be used
in the first two trimesters. It should be avoided if possible in the third trimester
because of a rare association with neonatal seizures. Other adverse effects in
neonates include irritability and tremor.
Loratadine and cetirizine (Category B) are now recommended as the
treatment of choice when any perceived risks are outweighed by potential
benefits.
Promethazine (FDA Category C) may interfere with several immunological
urinary pregnancy tests and also interferes with blood grouping in the ABO
system.
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Bilastine should be avoided in pregnancy, and the manufacturer of
rupatadine (FDA Category B) advises caution.
Most antihistamines can be found in breast milk to varying degrees but are
not known to be harmful. However, manufacturers advise avoiding their use
in mothers who are breastfeeding. Antihistamines may also inhibit lactation. If
chlorphenamine is taken during lactation, the infant should be monitored for
adverse effects (drowsiness and irritability).
++Essential patient information
Patients should be warned about the sedative effects of H1 antihistamines
and that additive CNS depression may occur if taken with other sedatives and
alcohol. The elderly may be more at risk. Sedation and impaired psychomotor
function can occur without a sensation of sleepiness.
Children
Doses are given in Table 1. Major side-effects of the older antihistamines
include drowsiness, although paradoxical stimulation may occur. Drowsiness
may reduce after a few days of treatment and is less of a problem with the
newer antihistamines.
Several newer antihistamines are licensed for use in children (see Table 1).
Cetirizine was safely used in a large cohort of children aged 12–24 months in
the Early Treatment of the Atopic Child (ETAC) Study.
H2 Antihistamines
There is controversy about the use of H2 antagonists in urticaria, although
some authors have found them useful when given in combination with H1
antagonists. This combination has been reported to be of benefit in symptomatic
dermographism and acute allergy syndromes. H1 and H2 receptor activation
can cause vasodilation and increased vascular permeability, while H1 receptors
mediate itch and flare. Theoretically therefore, H2 receptor antagonists may
reduce whealing. Their dermatological use is unlicensed and they should not
be used as monotherapy.
Ranitidine can be given at doses of 150 mg twice daily and is usually
choenrather than cimetidine, as it does not inhibit CYP450.
H2 antagonists should be given with caution in renal and hepatic impairment,
pregnancy and breastfeeding and cardiovascular impairment.
Adverse effects of ranitidine include rashes, altered bowel habit, dizziness,
somnolence or fatigue, confusion, headache, liver dysfunction, bradycardia or
atrio-ventricular block and blood disorders.
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Additional adverse effects of cimetidine include interstitial nephritis,
gynaecomastia, impotence and myalgia.
Like H1 antagonists, H2 antagonists have also been reported to cause
urticaria and angioedema.
Doxepin
Doxepin is a tricyclic antidepressant with potent H1 and H2 antihistamine
effects. Although unlicensed, it is a useful drug in the treatment of adult
urticaria and pruritus, particularly if night-time sedation is required. An initial
dose of 25 mg/d at night is usually sufficient, and may be adjusted to response.
An alternative low-dose regimen is 10 mg two or three times a day. Dosages
used in dermatology are usually much less than psychotropic dosage, which is
up to 300 mg daily. Anticholinergic and sedative effects are dose limiting in
these patients.
A topical formulation of doxepin is licensed for use as an antipruritic.
++Important drug interactions
Doxepin is metabolized by CYP450, and can prolong the QT interval, causing
arrhythmias and heart block. It should not be given with other drugs that do
the same (see above), or with monoamine oxidase inhibitors. It has multiple
drug interactions ( see formulary for further information).
++Adverse effects & their management
• Adverse effects include sedation, convulsions, hepatic and haematological
reactions, antimuscarinic effects (such as dry mouth, blurred vision, constipation and urinary retention), sweating, hypotension and syncope, hyponatraemia and weight gain.
• Due to its sedative effects and associated risk of falls, doxepin should be
used with caution in the elderly.
• Doxepin has also been reported to cause urticaria and angioedema. Topical
use of doxepin may cause allergic contact dermatosis.
• High doses of doxepin (150–300 mg/day) are associated with
electrocardiological abnormalities. Doses usually used in dermatology are
much lower. However, it should be used with caution or avoided in patients
with cardiac disease.
• Avoid in glaucoma, urinary retention, liver disease.
• Caution in epilepsy, thyroid disease.
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++Use in special situations
Pregnancy
Doxepin (FDA Category C; B for topical use) should not be used in pregnancy
because of limited available information.
Lactation
Doxepin should be avoided in lactation, since accumulation of metabolite may
cause sedation and neonatal respiratory depression.
Children
Doxepin is not recommended in children under 12 years.
With acknowledgements to Ruth Sabroe and Anne Kobza Black, authors of this
chapter in the 1st edition and Garrett Coman who reviewed this chapter for
the international perspective.
++Further reading
Lin RY, Curry A, Pesola GR, et al. Improved outcome in patients with allergic
syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg
Med 2000;36:462–8.
Mann RD, Pearce GL, Dunn N, et al. Sedation with ‘non-sedating’ antihistamines:
four prescription-event monitoring studies in general practice. Br Med J
2000;320:1184–6.
Smith PF, Corelli RL. Doxepin in the management of pruritus associated with
allergic cutaneous reactions. Ann Pharmacother 1997;31:633–5.
Zubier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA2LEN/EDF/WAO guideline:
management of urticaria. Allergy 2009;64:1427–43.
Bartra J, Valero AL, del Cuvillo A et al. Interactions of the H, antihistamines. J
invest Allergy Clin Immunol 2006;16(15):29–36.
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Antimalarials
Mark Goodfield
++Classification & mode of action
Antimalarials are the first choice oral therapy for all patients with cutaneous
lupus erythematosus (LE), as well as the majority with systemic forms of
the disease. They have been widely used since their introduction in 1894,
particularly since the 1950s.
Hydroxychloroquine, mepacrine and chloroquine are all effective in the
management of systemic lupus erythematosus (SLE), various forms of cutaneous
lupus and rheumatoid arthritis, and are also used in a variety of other cutaneous
disorders. They are safe when used appropriately, and generally well-tolerated:
they are probably under-prescribed.
Chloroquine and hydroxychloroquine are 4-aminoquinolones, while
mepacrine (quinacrine), a 9-aminoacridine, has an extra benzene ring but is
otherwise structurally similar. This structural change leads to a different sideeffect profile. The mode of action of antimalarials in dermatological disease
is still uncertain, although recent research has led to a clearer understanding
of their mode of action. Antimalarials inhibit toll-like receptors, particularly
TLR9 and TLR7, thus reducing levels of tumour necrosis factor (TNF)a and type
1 interferons, which are important mediators of inflammation in lupus. This
probably has more relevance to their efficacy than the previously reported
actions on phago/lysosomal function and interruption of antigen processing.
The antimalarials outlined above are well-absorbed orally and bind
particularly to pigmented tissues, including the retina. They are metabolized by
the liver and excreted renally, with a prolonged half-life of 40–50 days. There
is a great inter-individual variability in blood levels between patients taking
similar drug doses and the onset of therapeutic effect varies between drugs.
++Indications & dermatological uses
• All forms of cutaneous LE including discoid lupus erythematosus (DLE) and
subacute LE.
• SLE with disease symptoms including arthralgia, myalgia, fatigue, rashes
and alopecia.
• Other rheumatic diseases, including rheumatoid arthritis and juvenile
chronic arthritis.
Hydroxychloroquine and chloroquine are both licensed in the UK for treatment
of DLE and SLE, as well as ‘skin conditions aggravated by sunlight’. Mepacrine is
currently unlicensed for use in skin and connective tissue disorders.
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Several randomized, controlled trials provide evidence that antimalarials
are useful in suppressing disease activity in SLE, particularly skin manifestations
and fatigue. Fewer studies demonstrate efficacy in cutaneous lupus specifically.
Discontinuing hydroxychloroquine in stable SLE may lead to increased disease
activity. The drugs may also reduce the risk of thrombotic episodes in patients
with antiphospholipid antibody syndrome, and reduce serum lipids.
In addition to cutaneous lupus, other evidence-based dermatological
indications for antimalarials include:
• Polymorphic light eruption.
• Cutaneous sarcoidosis.
• Porphyria cutanea tarda.
Quinolone antimalarials have also been found to be useful in benign cutaneous
lymphocytic infiltration (Jessner’s), reticular erythematous mucinosis syndrome,
dermatomyositis, urticarial vasculitis, alopecial areata and lichen planus.
++Formulations/Presentation
• Hydroxychloroquine is available as 200 mg tablets.
• In the UK, chloroquine is dispensed as 250 mg tablets of chloroquine
­phosphate (containing 150 mg chloroquine base).
• Chloroquine sulphate syrup is available at a concentration of 68 mg/5 mL
(containing 50 mg/5 mL chloroquine base). Chloroquine sulphate is currently difficult to obtain in tablet form.
• Chloroquine sulphate 250 mg and 500 mg tablets are the most readily
­available forms in the USA.
• Mepacrine hydrochloride is available as 100 mg scored tablets.
++Dosages & suggested regimens
There is little evidence of comparative efficacy of different antimalarials in
skin disease, but hydroxychloroquine is used in preference to chloroquine
due to its safety profile. Most patients will need repeated courses of therapy,
or even continuous treatment, to deal with flares and adequately suppress
disease. Cigarette smoking seems to impair the efficacy of antimalarials, but
the ­mechanism remains unclear. Combinations of antimalarials, particularly
­hydroxychloroquine and mepacrine, are more effective than either alone.
Hydroxychloroquine sulphate
Initial dose: 400 mg daily; maintenance dose: 200–400 mg daily; maximum dose:
400 mg daily or 6.5 mg/kg ideal bodyweight. In obese patients it is important
to calculate the ideal bodyweight in order to avoid excess dosage. Tablets are
not scored, but due to a long half-life, the daily dosage can be varied (e.g. 200
mg day 1 then 400 mg day 2 etc.) to avoid exceeding recommended limits.
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The onset of effect is slow, because of tissue distribution in fat and the
mode of action, and may take up to 12 weeks. Beneficial effects take a similar
period to wear off. Approximately 60% of patients with DLE respond within
6 months, but there may be some loss of efficacy with continued treatment,
requiring the addition of mepacrine to regain disease control.
Mepacrine hydrochloride
The usual dosage is 50–100 mg daily, but doses up to 400 mg daily have been
used. Yellow skin discolouration is inevitable and may be severe at higher
doses. The onset of action is about 3–6 weeks. It may be used as monotherapy
or combined with hydroxychloroquine
Chloroquine phosphate or sulphate
Chloroquine base is usually given at a dose of 150 mg daily (= 200 chloroquine
sulphate or 250 mg chloroquine phosphate). The maximum recommended
dose is 2.5 mg/kg/d based on ideal bodyweight. Its onset of action is more
rapid and may be as short as 1 month.
Chloroquine carries a higher risk of retinopathy (see Adverse effects &
their management) than hydroxychloroquine, possibly because it crosses
the blood–retinal barrier more easily, so it should be used only after other
antimalarials have failed. There are inadequate data on chloroquine to advise
a safe maximum dose and cumulative dosage may be important, so treatment
is usually limited to courses of 6 months.
++Baseline investigations & considerations
The 2009 Royal College of Ophthalmologists recommendations for good
practice in rheumatology and dermatology for hydroxychloroquine are as
follows:
• Ask about visual impairment (which is not corrected by glasses). Examine near visual acuity of each eye (with glasses where appropriate). If the
patient cannot read N.5 or N.6 on the reading chart (with reading glasses
on), a referral should be made, first to an optician to correct any refractive
error, then to an ophthalmologist if the impairment is still present. (See
­Appendix 2 for reading chart.)
• FBC (CBC), renal indices and LFTs.
++Monitoring
• Monitor patients annually, enquiring about visual symptoms, rechecking
acuity and assessing for blurred vision using the reading chart. Referral to
an ophthalmologist is recommended in the following situations:
• Visual impairment or eye disease detected at baseline.
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•
•
Development of changed acuity or blurred vision (as assessed by reading
chart) while on treatment.
Patients who ultimately require long-term treatment (>5 years).
Special point
The American Academy of Ophthalmology (AAO) provided updated guidelines
for the ophthalmic monitoring of patients on hydroxychloroquine in 2011.
Baseline screening is recommended as both a reference point as well as
to rule out undiagnosed maculopathy, which may preclude the use of
hydroxychloroquine. Annual screening should begin after 5 years of therapy
(or upon onset of therapy in those with maculopathy or unusual risk factors as
defined by the AAO) and should include at least an objective test (multifocal
electroretinogram, spectral domain optical coherence tomography or fundus
autofluorescence) in addition to a 10-2 visual field. mfERG can be used in the
place of a visual field. Clinical examination is also important, although should
not be relied upon for detection of maculopathy as gross changes in macular
appearance represent late stage disease. The AAO guidelines represent the
most comprehensive, up-to-date and evidence based framework for screening
for ophthalmic complications of hydroxychloroquine toxicity (see further
reading). The above guidelines are only for adults; no specific guidelines have
been provided by ophthalmic societies in the screening of paediatric patients.
• Haematology and biochemistry.
Mepacrine: FBC (CBC) every 3 months.
Hydroxychloroquine and chloroquine: FBC, renal and LFTs every 6 months.
++Contraindications
Hydroxychloroquine and chloroquine should be avoided in individuals with a
history of hypersensitivity to either drug. (Mepacrine is not contraindicated.)
++Cautions
• Avoid if possible in patients with pre-existing maculopathy, e.g. age related
macular degeneration. The decision to start this medication in a patient
with maculopathy should be done in close co-ordination with their ophthalmologist.
• Hepatic impairment.
• Renal impairment: mild-moderate – the doses should be reduced (hydroxychloroquine, for example may be reduced to 200 mg three times a week).
Avoid in severe renal impairment (glomerular filtration rate [GFR] <10 mL/
min). Routine therapeutic blood monitoring is not currently available for
antimalarials.
• Neurological disorders, especially epilepsy.
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•
•
•
•
Myaesthenia gravis may be exacerbated.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Intermittent and variegate porphyria.
The elderly due to reduced renal and hepatic function.
++Important drug interactions
• Antacids reduce absorption of hydroxychloroquine and chloroquine.
• Chloroquine and hydroxychloroquine increase the risk of ventricular
­arrhythmias with amiodarone.
• Cimetidine may decrease the metabolism of chloroquine, and increase its
plasma levels.
• Chloroquine and hydroxychloroquine antagonize the action of antiepileptic
drugs.
• Chloroquine and hydroxychloroquine increase plasma levels of digoxin.
• Chloroquine and hydroxychloroquine increase plasma ciclosporin (cyclosporine) concentration.
• Penicillamine plasma concentration and toxicity may be increased by both
chloroquine and hydroxychloroquine.
++Adverse effects & their management
• Ocular adverse effects, specifically an irreversible retinopathy with blindness, are the major risk associated with chloroquine and hydroxychloroquine treatment. The maculopathy may progress even after the cessation
of the drug. Low dose hydroxychloroquine carries a very small risk of this
complication, while mepacrine has negligible ocular toxicity.
Early retinopathy with antimalarials takes the form of a non-specific fine
pigmentary stippling in the macular area and loss of the foveal light reflex. This
may develop into irreversible bull‘s eye maculopathy and widespread retinal
pigment epithelial atrophy, associated with a central scotoma, loss of visual
­acuity and peripheral visual field loss. Corneal deposits, and impairment of
accommodation are reversible, dose related side-effects.
The incidence of clinically significant retinopathy with hydroxychloroquine
is low and appears related to long-term treatment (>5 years). It remains unclear
if cumulative dosage or duration of treatment is of most relevance. Toxicity
has been reported to increase sharply after a cumulative dose of 1000 g
hydroxychloroquine; intermittent treatment, for example for 6 months, is
therefore preferred. Many patients with cutaneous lupus can be adequately
managed by limiting antimalarial therapy to the spring and summer seasons.
Risk factors are listed in Table 1 (overleaf).
If visual abnormalities or symptoms occur the drug should be discontinued and
the patient monitored for possible progression after cessation of therapy.
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TABLE 1 Risk factors for hydroxychloroquine retinopathy
Duration
>5 years
Cumulative dosage
>1000 g
Age
Elderly
Co-morbidities
Renal, hepatic impairment, obesity
Ocular disease
Retinal or macular complaints
• Common adverse effects include gastrointestinal (GI) disturbance, headache and pruritus. These are usually mild. More serious but rare adverse
effects include hepatic damage, myopathy, neuropathy and psychosis.
• Cutaneous adverse effects include skin and mucous membrane pigmentation, depigmentation of hair, alopecia and exfoliative dermatitis. Serious
cutaneous adverse reactions including acute generalized exanthematous
pustulosis (AGEP) and toxic epidermal necrolysis have been reported with
hydroxychloroquine. Mepacrine causes reversible yellow discolouration of
the skin when used in maintenance doses of 100 mg daily, and may occasionally cause severe lichenoid eruptions (preceded by itch). Psoriasis may be
worsened by chloroquine and hydroxychloroquine.
• Haematological adverse effects of antimalarials include a small but significant risk of marrow suppression, and haemolysis in G6PD deficiency.
• Overdosage: antimalarials are very toxic in overdose, especially in infants,
so safe storage is essential.
++Use in special situations
Pregnancy
The use of hydroxychloroquine (FDA Category C) is pregnancy is controversial.
The manufacturers recommend avoidance of hydroxychloroquine in pregnancy
and breastfeeding, because of a theoretical risk of cochlear damage. However,
stopping hydroxychloroquine when pregnancy is discovered makes little sense
because of the long half-life. Separate studies in the UK and North America
have found that continuation of hydroxychloroquine in pregnant patients with
SLE is probably safe. There is considerable experience of pregnancy in patients
safely receiving antimalarials as prophylaxis in malaria endemic regions, and
UK obstetricians are happy to continue hydroxychloroquine in patients in in
vitro fertilization (IVF) programmes.
Chloroquine (FDA Category D) is contraindicated in pregnancy, except
for treating and preventing malaria. Because mepacrine is unlicensed, the
manufacturers have no data on its use in pregnancy and breastfeeding.
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Lactation
Small amounts of antimalarials are excreted in breast milk, therefore mothers
taking these drugs should not breastfeed. However, the same is true for lactation
as pregnancy, in terms of experience obtained from malarial prophylaxis.
Children
Quinolones and mepacrine are not licensed for use in children. When essential,
hydroxychloroquine should be used at the minimum e
­ ffective dose and not
exceed 6.5 mg/kg/d or 400 mg. Tablets of 200 mg can therefore not be used in
children weighing <31 kg. Chloroquine is sometimes used in specialist units at
a daily dose of 4 mg/kg/d for ease of administration.
++Essential patient information
• Patients should be warned to stop treatment and seek advice from the
prescribing doctor if they develop visual symptoms such as reduced acuity,
abnormal colour vision or blurred vision.
• Patients prescribed chloroquine should be specifically counselled about the
risk of permanent visual loss.
With acknowledgements to Thomas Millard and Graham Hughes, authors of
this chapter in the 1st edition, and Bob Modjtahedi who reviewed this chapter
from the international perspective.
++Further reading
Abarientos C, Sperber K, Shapiro DL, et al. Hydroxychloroquine in systemic
lupus erythematosus and rheumatoid arthritis and its safety in pregnancy.
Expert Opin Drug Saf 2011;10;705–14.
Jover JA, Leon L, Pato E, et al. Long-term use of antimalarial drugs in rheumatic
diseases. Clin Exp Rheumatol 2012;30;380–7.
Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of
Ophthalmology. Revised recommendations on screening for chloroquine and
hydroxychloroquine retinopathy. Ophthalmology 2011;118:415–22.
Royal College of Ophthalmologists. Hydroxychloroquine and ocular toxicity
recommendations on screening. October 2009.
Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with
impaired interferon-alpha and tumor necrosis factor-alpha production by
plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther
2012;14;R155.
Toubi E, Rosner I, Rozenbaum M, Kessel A, Golan TD. The benefit of combining
hydroxychloroquine with quinacrine in the treatment of SLE patients. Lupus
2000;9:92–5.
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Wahie S, Daly AK, Cordell HJ, et al. Clinical and pharmacogenetic influences on
response to hydroxychloroquine in discoid lupus erythematosus: a retrospective
cohort study. J Invest Dermatol 2011;131:1981–6.
Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights
into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev
Rheumatol 2012;8:522–33.
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Antivirals
for HerpesViruses
David J. Eedy
++Classification & mode of action
Herpesviruses are members of a large family of DNA viruses that cause disease
in humans and animals. At least five species are extremely widespread in
humans, namely herpes simplex virus (HSV-1 and HSV-2) (both of which can
cause orolabial and genital infections), varicella zoster virus (VZV) (that causes
chickenpox and shingles), Epstein–Barr virus (EBV) (the cause of infectious
mononucleosis), and cytomegalovirus (CMV). HSV and VZV are neurotropic
and following primary infection, establish long-term asymptomatic latency in
the ganglia of sensory nerves. Reactivation of latent virus leads to enhanced
replication and cell lysis and disease symptoms. Other human herpesviruses
establish latency in lymphoid cells and can play a role in oncogenesis.
Most viral illnesses including HSV and VZV are self-limiting and do not require
specific antiviral therapy. However, occasionally serious complications such as
encephalitis and disseminated infections can occur, especially in neonates or
immunocompromised patients (such as transplant recipients, cancer patients
and those with human immunodeficiency virus [HIV] infection), and exposure
to VZV infection in early pregnancy results in congenital varicella syndrome in
up to 5% of pregnancies.
Antiherpes drugs inhibit viral DNA synthesis and viral replication by
inhibiting viral DNA polymerase, which results in premature chain termination.
Aciclovir (acyclovir) is the prototype guanosine analogue antiherpes drug and
requires activation by viral thymidine kinase. It has a low water solubility and
poor gastrointestinal (GI) absorption, with low oral bioavailability (15–30%) so
i/v administration is required to achieve consistent high plasma levels. The poor
oral bioavailability is improved by esterification to the pro-drug valaciclovir
(valacyclovir), which is hydrolysed to aciclovir (acyclovir) via hepatic firstpass metabolism and increases the bioavailability 3–5-fold to approximately
70%. The superior pharmacokinetics of valaciclovir allows a reduced dosage
frequency that may improve clinical efficacy and compliance. The therapeutic
activity of aciclovir against herpesviruses is as follows: HSV >VZV >EBV >CMV.
Penciclovir has a similar spectrum of activity and potency against HSV
and VZV but due to a very low oral bioavailability it is only used topically.
Famciclovir is a pro-drug of penciclovir that improves the oral bioavailability
of penciclovir to over 70%. The active triphosphate form of penciclovir has
been shown to have more persistent antiviral activity in HSV infected cells than
aciclovir, and this may lead to an increase in efficacy.
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Drug resistance is an emerging threat to the clinical utility of antiviral
drugs, especially following their long-term use in immunocompromised
patients. Aciclovir resistance in HSV is usually associated with mutations in
the viral thymidine kinase gene, rather than DNA polymerase, as this enzyme
is not essential for viral replication. Strains resistant to aciclovir are almost
always cross-resistant to penciclovir and famciclovir. Resistant infections can
be managed by foscarnet or cidofovir, but both are more toxic than aciclovir.
Foscarnet is inhibitory for all herpesviruses and HIV and inhibits viral nucleic
acid synthesis by interacting directly with viral DNA polymerase or reverse
transcriptase. Foscarnet resistant strains of herpesvirus have been described
and in this situation i/v cidofovir should be considered (an unlicensed use).
++Indications & dermatological uses
• Aciclovir is licensed for use in HSV and VZV infection.
• Valaciclovir is licensed for HSV and VZV infection and CMV prophylaxis in
organ transplant recipients.
• Famciclovir is licensed for use in shingles and genital herpes.
• Foscarnet is licensed for unresponsive HSV infection in immunocompromised patients and CMV retinitis in HIV patients.
HSV infection
Primary HSV infection of the mouth and lips (gingivostomatitis) or eyes in
immunocompetent individuals is usually managed with topical aciclovir or
penciclovir. Oral aciclovir may provide modest clinical benefit in preventing
subsequent recurrent orolabial herpes. Severe infection, neonatal HSV and
immunocompromised individuals require systemic therapy.
Primary and recurrent genital HSV infection is usually treated with an
oral antiviral drug. This reduces virus shedding, symptoms and healing time,
but does not significantly reduce the risk of further recurrence. Long-term
prophylactic therapy with aciclovir or valaciclovir may be considered in patients
with frequently recurring, debilitating genital herpes which is impairing the
quality of life. It reduces the rate of clinical recurrence by about 90% and
subclinical shedding is markedly reduced, but not eliminated. Aciclovir has
been used safely for up to 10 years. Shorter-term prophylaxis (e.g. special
events or risk periods) reduces the overall risk of recurrence by about 70% in
those with sun-induced recurrences of HSV.
Long-term HSV prophylactic regimes may also be useful in the treatment
of disabling recurrences of herpetic whitlow and HSV related erythema
multiforme.
Prophylactic oral aciclovir is used in late pregnancy (from 36 weeks) to
reduce viral shedding in females with recurrent genital herpes and prior to
organ transplantation.
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VZV infection
In healthy children, primary infection with VZV (chickenpox) is usually benign
and self-limiting. However, in adolescents and adults chickenpox is more severe
and oral antiviral therapy should be started within 24 hours of onset of the rash.
This shortens the healing time and duration of fever and symptoms. Starting
aciclovir after this time point appears to be of no value in uncomplicated adult
varicella.
Systemic therapy is recommended for immunocompromised patients to
reduce the risk of pneumonitis. Pregnant females and immunocompromised
patients who are not immune to VZV require specialist advice and may require
urgent treatment with varicella zoster immunoglobulin following exposure to
chickenpox.
Oral antiviral treatment is indicated in herpes zoster (shingles) to reduce
the severity and duration of acute pain, reduce complications (post-herpetic
neuralgia) and reduce viral shedding. Treatment should be started within
72 hours of the onset of the rash. Additional treatment with prednisolone may
accelerate resolution of acute pain but does not reduce post-herpetic neuralgia.
Valaciclovir and famciclovir have been shown to be superior to aciclovir in
reducing herpes zoster associated pain and are generally preferred due to their
more convenient dosing regimens. Administration of aciclovir i/v increases the
rate of healing and resolution of acute neuritis in immunocompetent patients
with shingles compared with oral therapy, but does not appear to confer any
improved long-term benefits.
Immunocompromised patients require i/v therapy for 7 days to reduce the risk
of disseminated VZV infection. In those who are severely immunocompromised
oral therapy may be administered for 6 months.
++Formulations/Presentation
• Aciclovir: 200 mg and 800 mg tablets; 200 mg, 400 mg and 800 mg ­dispersible
tablets; and suspensions of 200 mg/5 mL, 400 mg/5 mL (with sugar-free
­versions available). Powder to reconstitute for slow i/v infusion. Topical
­aciclovir 5% cream and 3% eye ointment.
• Valaciclovir: 250 mg and 500 mg tablets.
• Famciclovir: 125 mg, 250 mg and 500 mg tablets.
• Penciclovir: 1% cream for herpes labialis. Not recommended under 12 years.
• Foscarnet sodium is only available as a solution for i/v infusion.
++Dosages & suggested regimens
Non-genital HSV infection (primary gingivostomatitis/herpes labialis).
oral aciclovir:
• Adults and children over 2 years: 200 mg 5×/d for 5 days (double the dose if
immunocompromised or absorption impaired).
• Infants aged 1 mo–2 y: half adult dose.
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Intravenous aciclovir is recommended to achieve higher blood levels than
oral aciclovir in severe infections (disseminated infection, extensive eczema
herpeticum, neonatal infection, HSV encephalitis):
• Adults and children over 12 years: 5 mg/kg tds for 5 days. Obese individuals
should receive a dosage based on their ideal bodyweight.
• Neonates, infants and children up to 12 years: see children's formulary for
dosage according to body surface area or bodyweight.
Valaciclovir:
• Adults: 500 mg bd for 5 days (up to 10 days if new lesions appear or healing
incomplete; double the dose in immunocompromised).
• Adults and children over 12 years: two 2 g doses with a 12 hour interval for
treatment of acute herpes labialis.
Primary genital HSV infection
• Oral aciclovir: 200 mg 5×/d or 400 mg tds for 5 days (longer if new lesions
­appearing). Increase dose to 400 mg 5×/d in immunocompromised.
• Valaciclovir: 500 mg bd for 5 days (up to 10 days if new lesions appear or
healing incomplete; double the dose in immunocompromised).
• Famciclovir: 250 mg tds for 5 days.
Recurrent genital HSV infection
• Oral aciclovir: 200 mg 5×/d, 400 mg tds for 3–5 days or 800 mg tds for 2
days. In immunocompromised, give 400 mg tds for 5–10 days.
• Valaciclovir: 500 mg bd for 3–5 days (double the dose and treat up to 10
days in immunocompromised).
• Famciclovir: 125 mg bd for 5 days or 1 g bd for 1 day (500 mg bd for 5–10
days in immunocompromised).
Alternatively, topical therapy with aciclovir or penciclovir may be used for
recurrent HSV. Treatment should be commenced at the onset of symptoms.
Penciclovir is not recommended under the age of 12 years.
Prophylactic regimens for frequently recurring genital herpes
• Short-term prophylaxis: aciclovir 400 mg bd for 1 week.
• Long-term prophylaxis: aciclovir (400 mg bd or 200 mg tds); valaciclovir
500 mg once daily (increase to twice daily for very frequent recurrences);
famciclovir 250 mg bd. Long-term prophylactic therapy is usually interrupted after 6–12 months to assess recurrence frequency.
Primary VZV infection (chickenpox)
• Oral aciclovir: 800 mg 5×/d for 7 days, in both normal and immunocompromised patients.
Herpes zoster (shingles)
• Oral aciclovir: 800 mg 5×/d for 7 days for adults and children over 12 years.
In severely immunocompromised patients 800 mg qds can be administered
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for up to 6 months. In younger children, 20 mg/kg (up to 800 mg) qds
­(unlicensed).
• Intravenous aciclovir: 10 mg/kg tds for acute herpes zoster affecting the
trigeminal nerve (forehead and eyelids).
• Valaciclovir: 1g tds for 7 days in adults and immunocompromised children
over 12 years.
• Famciclovir: 500 mg tds for 7 days (or 10 days in immunocompromised) or
750 mg 1–2×/d for 7 days.
Aciclovir resistant HSV and VZV
Foscarnet sodium i/v 40 mg/kg tds by slow infusion for 2–3 weeks or until lesions
healed. It is licensed for use in aciclovir resistant mucocutaneous HSV infections
and may also be effective in aciclovir resistant VZV infections.
Special point
Chickenpox vaccination, with live attenuated VZV, is not part of the current
routine UK childhood immunization programme. It is recommended for
non-immune healthcare workers, older children/adults and close family
contacts of immunocompromised individuals.
Passive immunity is conferred by administration of varicella zoster
immunoglobulin, which should be given to high risk individuals within 4 days
of contact (British National Formulary [BNF] advises 10 days) with chickenpox
or herpes zoster. High risk individuals include neonates, non-immune pregnant
females and immunocompromised patients – including those who have received
systemic corticosteroids in the previous 3 months (>40 mg prednisolone daily
for more than 1 week).
Despite recent attempts, no effective vaccine has yet been developed for
HSV infection.
++Baseline investigations & considerations
• Routine monitoring is not required for aciclovir, valaciclovir and famciclovir.
• Foscarnet: renal indices, electrolytes, calcium and magnesium.
++Monitoring
Renal indices, electrolytes, calcium and magnesium should be monitored
frequently during foscarnet therapy.
++Contraindications
Hypersensitivity to the antiviral agent.
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++Cautions
• Aciclovir i/v: maintain adequate hydration and reduce dose in renal failure.
Dose limiting toxicities of i/v aciclovir are renal insufficiency and CNS sideeffects.
• Valaciclovir; caution with high doses in hepatic impairment and reduce dose
of i/v infusion in renal failure.
• Famciclovir: reduce dose in renal impairment.
• Aciclovir and penciclovir creams can cause transient stinging, burning or
numbness. They should not be used in the mouth.
++Important drug interactions
• Aciclovir and valaciclovir: increased nephrotoxicity with ciclosporin
­(cyclosporine) and possibly with tacrolimus.
• Increased plasma concentrations of aciclovir with mycophenolate.
• Excretion of aciclovir reduced by probenecid.
• Plasma concentrations of theophylline may be increased.
• Excretion of famciclovir is possibly reduced by probenecid.
• Foscarnet with pentamidine isetionate increases the risk of hypocalcaemia.
++Adverse effects & their management
Oral antiherpes virus drugs are generally well-tolerated.
• Aciclovir has been infrequently associated with nausea, diarrhoea, rash,
headache, pruritus, photosensitivity and very rarely renal insufficiency, hepatitis, jaundice, neuropsychiatric effects (dizziness, confusion, drowsiness,
hallucinations psychosis, convulsions), tremor and fever. Anaemia, thrombocytopenia or leukopenia have been described.
• Valaciclovir has similar adverse effects but in higher dose may be associated with confusion, hallucinations, nephrotoxicity and uncommonly severe
thrombocytopenic syndromes, especially in immunocompromised patients.
• Famciclovir may be associated with headache, diarrhoea and nausea. Urticaria, rash and hallucinations or confusion (predominantly in the elderly)
have been reported.
• Intravenous foscarnet may cause a range of adverse effects including GI
effects, neuropsychatric disturbance, renal impairment and bone marrow
toxicity. It requires careful monitoring for electrolyte disturbance especially
hypocalcaemia.
• Aciclovir and penciclovir creams can cause transient stinging, burning or
numbness. Ophthalmic use of aciclovir can give rise to local irritation and
rarely, blepharitis or very rarely hypersensitivity.
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++Use in special situations
Pregnancy
• Aciclovir and valaciclovir (both FDA Category B) are not known to be harmful in pregnancy, but the manufacturers advise to use only when potential
benefits outweigh risk. No increase in the frequency of congenital abnormalities has been recognized in infants born to females who took aciclovir
during pregnancy, and the drug has been used safely in neonates.
• Famciclovir (FDA Category B): avoid but use only when potential benefits
outweighs risk.
• Foscarnet (FDA Category C): avoid use.
Lactation
• Aciclovir and valaciclovir: significant amounts are found in milk; it is not
known to be harmful but should be used with caution.
• Famciclovir: insufficient data exist.
• Foscarnet: avoid.
Children
• Aciclovir is licensed for use in children and is the treatment of choice.
• Valaciclovir is licensed for use in children over 12 years for CMV infection.
• Famciclovir is not licensed for children and not generally recommended due
to limited safety data.
• Foscarnet is not licensed for use in children. Dosages of 40 mg/kg tds can be
given for severe mucocutaneous HSV infection
++Essential patient information
Patients should be advised about additional symptomatic treatment of their
infection with oral analgesics and to maintain adequate fluid intake. It should
be explained that a person who has not had chickenpox or the varicella vaccine
can catch chickenpox from a person with shingles and that the person is
infectious until their lesions have dried (usually 5–7 days). While chickenpox is
spread by respiratory droplets and skin contact, only direct skin contact with
shingles carries the risk of infection.
Seek urgent specialist advice for ocular infection with cold sores or shingles.
With acknowledgements to Stephen K. Tyring who reviewed this chapter from
an international perspective.
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++Further reading
Andrei G, Snoek R. Advances in the treatment of varicella-zoster virus infections.
Adv Pharmacol 2013;67:107–68.
Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the
management of herpes zoster. Clin Infect Dis 2007;44(Suppl. 1):S1–S26.
McDonald EM, deKock J, Ram FS. Antivirals for management of herpes zoster
including ophthalmicus: a systematic review of high-quality randomized
controlled trials. Antivir Ther 2012;17:255–64.
Piret J, Boivin G. Mini review. Resistance of herpes simplex viruses to nucleoside
analogues: mechanisms, prevalence and management. Antimicrob Agents
Chemother 2011;55(2):459–72.
Sacks S, Aoki FY. Famciclovir for the management of genital herpes simplex in
patients with inadequate response to aciclovir or valaciclovir. Clin Drug Invest
2005;25:803–9.
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Azathioprine
Sarah H. Wakelin
++Classification & mode of action
The synthetic purine analogue azathioprine (AZA) was initially developed as
an immunosuppressant in the 1960s, but is now most widely prescribed for
its anti-inflammatory actions, especially in the treatment of skin and bowel
disease and lupus.
AZA is a pro-drug and after oral ingestion and absorption it is rapidly
hydrolysed non-enzymatically to an imidazole derivative (methlynitroimidazole)
and 6-mercaptopurine (6-MP). Although 6-MP is also available for oral
administration, AZA is usually preferred as its bioavailability is more reliable.
6-MP undergoes metabolism by competing enzymatic pathways to form
various active metabolites (thioguanine nucleotides) and inactive metabolites
(Figure 1). Thioguanine nucleotides are incorporated into the DNA and have
an antiproliferative effect, especially on lymphocytes and other haemopoietic
cells. The principal deactivating pathways are regulated by the enzymes
thiopurine methyltransferase (TPMT) and xanthine oxidase (XO). Impairment
of these pathways, due to inherent low enzyme activity or drug interactions
can lead to accumulation of potentially toxic levels of thioguanine nucleotides
and the risk of life-threatening bone marrow suppression. Tests to measure
TPMT activity are now widely available and play a key role in the safe and
effective prescribing of AZA.
TPMT
AZA
6-MP
XO
HGPRT
TPMT
XO
HGPRT
AZA
MP
6-methyl MP
6-thiouric acid
6-thioguanine nucleotides
= thiopurine methyl transferase
= xanthine oxidase
= hypoxanthine phosphoribosyl transferase
= azathioprine
= mercaptopurine
FIGURE 1 Metabolism of azathioprine via different enzyme pathways. Active
­metabolites are boxed.
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Azathioprine
++Indications & dermatological uses
The UK licensed indications for AZA are listed below. There are no FDAapproved dermatological indications in the USA.
• Pemphigus vulgaris.
• Systemic lupus erythematosus.
• Dermatomyositis/polymyositis.
AZA has also been widely used as a steroid-sparing treatment for bullous
pemphigoid, and in this context appears to have similar efficacy to
mycophenolate mofetil. Good clinical evidence supports its use as an oral
monotherapy in the treatment of atopic dermatitis and it has been shown
to be of benefit in chronic actinic dermatitis and parthenium allergic contact
dermatitis.
AZA is also used to treat a range of vasculitides including Wegener’s
granulomatosis, Behçet’s disease, Henoch–Schönlein purpura and severe
cutaneous leukocytoclastic vasculitis. Small studies have reported benefit in
pyoderma gangrenosum, lichen planus, erythema multiforme and pityriasis
rubra pilaris.
++Formulations/Presentation
• Generic and branded formulations tablet sizes of 25 mg and 50 mg.
• Preservative-free powder to reconstitute for i/v injection.
++Dosages & suggested regimens
The onset of action is slow, and therapeutic effects may take several months.
Empirical dosing of 1–3 mg/kg/d is recommended in the package insert, with
adjustment within these limits according to response and side-effects. This may
be given as a single or divided dose and taken with food to reduce gastric
upset.
Use of a low starting dose of 0.5–1 mg/kg/d for the first 4 weeks may
minimize the risk of side-effects such as nausea. Dosage may then be increased
according to baseline TPMT levels and the FBC (CBC), especially the white blood
cell count (WBC).
Several UK authors have recommended a schedule for maintenance doses
based on TPMT activity as in Table 1. Units of measurement and category
boundaries may differ in other countries and prescribers are advised to contact
their laboratory for further advice.
Patients with absent TPMT activity should not receive AZA (see Baseline
investigations & considerations). In exceptional situations a greatly reduced
dose (5–10%) has been used with very close haematological and metabolite
monitoring. The effects of treatment may also be slow to wear off after ceasing
treatment due to persistence of active drug metabolites. Therapy should be
discontinued if there is no improvement after 3 months.
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TABLE 1 Recommended dosages of azathioprine (AZA) based on thiopurine methyltransferase (TPMT) activity
TPMT range
Maintenance AZA dose mg/kg
Absent
<10 pmol/h/mg Hb
Contraindicated
Intermediate/carrier
10–25 pmol/h/mg Hb
1.0–1.5
Normal/high
>26 pmol/h/mg Hb
2.0–3.0
++Contraindications & cautions
• Hypersensitivity to AZA or 6-MP is an absolute contraindication as AZA
­hypersensitivity syndrome is potentially life-threatening.
• Very low/absent or unknown TPMT levels (see Baseline investigations &
­considerations).
The following contraindications are also listed in the package insert:
• Severe infection.
• Pancreatitis.
• Severely impaired hepatic function or bone marrow depression.
• Pregnancy (unless benefits outweigh risks).
• Lactation.
• Malignancy is a contraindication to any form of immunosuppression including AZA, due to the possible increased risk of disease progression.
Human immunodeficiency virus (HIV) infection is not a contraindication and
there is growing experience of safe use of AZA and other immunosuppressive
drugs in HIV-positive patients. In this situation, it is used in those who are
stabilized on highly active antiretroviral therapy (HAART). HIV screening should
be considered prior to starting AZA and close liaison carried out with infectious
disease specialists prior to initiating therapy in HIV-positive individuals.
Hepatitis B virus (HBV) is an important consideration as up to one-third of
the world’s population has evidence of past or active infection with this virus.
HBV carriers are at risk of a disease flare on treatment with immunosuppressants
and acute liver failure on drug withdrawal. Screening for HBV surface antigen
(HBsAg) and anti-HBV core antibodies (antiHBc) should be considered in all
patients and non-immune individuals at risk of infection should receive
immunization against HBV. Testing LFTs alone is inadequate as these may be
normal in infected individuals. The risk for hepatitis C virus (HCV) infected
individuals is unclear, but all patients seropositive for HBV and HCV should be
discussed with a hepatologist or infectious disease specialist as prophylactic
antiviral therapy may be required (see Systemic Therapy & Liver Disease).
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++Important drug interactions
• Angiotensin converting enzyme (ACE) inhibitors may increase the risk of
anaemia or leukopenia in those with renal impairment.
• Allopurinol inhibits XO and leads to accumulation of active metabolites
with potentially life-threatening myelotoxicity. If co-administration is
essential, it has been suggested that the dose of AZA should be reduced to
one-quarter or one-third of the routine dose, with very careful
haematological ­monitoring.
• Live-attenuated vaccines (see Table 2) should not be given to patients
receiving AZA or other immunosuppressants. Inactivated vaccines are safe.
(See Department of Health Green book for latest UK recommendations on
vaccines and vaccination.)
• Ribavirin inhibits an enzyme in the purine salvage pathway and has been
reported to cause severe pancytopenia.
• Warfarin resistance has been reported, and increased warfarin dosing may
be required with close monitoring of anticoagulation.
• Other drugs that can cause bone marrow depression should be avoided,
including other immunosuppressants, trimethoprim, cotrimoxazole and
­clozapine.
TABLE 2 Live-attenuated vaccines
BCG
Intranasal influenza vaccine
Measles, mumps, rubella
Oral polio
Oral typhoid
Varicella zoster (chickenpox)
Yellow fever
++Baseline investigations & considerations
•
•
•
•
•
•
FBC (CBC).
Urea, electrolytes and creatinine.
LFTs
TPMT activity (see Dosages & suggested regimens).
Hepatitis B & C serology.
HIV testing if at risk.
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• Varicella zoster virus (VZV) serology in patients without reliable history of
chickenpox. VZV vaccine should ideally be given to the non-immune several
weeks prior to starting AZA (as it is a live vaccine), but the disadvantages of
delaying immunosuppressant therapy may not be justified.
• Influenza and pneumococcal vaccination are recommended for people
who are on immunosuppressant medication. Ideally these inactive vaccines
should be administered at least 2 weeks before therapy is started.
• Cervical screening should be up-to-date. A pre-treatment gynaecological
review is recommended in females with a history of cervical intraepithelial
neoplasia (CIN) as immunosuppressants increase the risk of progression to
invasive disease and reduce the success of treatment.
• Dermatological examination and treatment of skin cancer and actinic
keratoses is recommended for transplant recipients and seems appropriate
for all patients in whom long-term treatment is likely.
• TPMT activity testing may be unreliable for up to 60 days after red cell
transfusions due to interference by donor TPMT activity. Diuretics, some
non-steroidal anti-inflammatory drugs (NSAIDs) and aminosalicylates
such as sulfasalazine may have inhibitory effects on TPMT but the clinical
relevance of these is unclear.
++Monitoring
• Weekly FBCs for the first 8 weeks then monthly or no less than every 3
months (manufacturer’s recommendations). Any downward trend in the
neutrophil count should be noted, as an early decrease that is still within
the normal total WBC range may herald more severe neutropenia.
• There is no recommended schedule for monitoring renal or liver function,
but they should be checked regularly during the first few months of therapy
(e.g. every 1–2 weeks) as hepatotoxicity can be seen during this period. In
patients stabilized on therapy, FBC and LFTs should be checked at least
every 3 months.
• Measurement of thioguanine nucleotides is not routinely undertaken
in dermatology but may be useful to assess adherence and guide dose
adjustment. Levels of thioguanine nucleotides have been found to correlate
with clinical remission rates in patients with inflammatory bowel disease
(IBD).
++Adverse effects & their management
• Gastrointestinal: nausea is the commonest adverse effect of AZA and usually
settles with continued treatment. It may be helped by dividing the daily
dose and taking medication with food or co-prescription of an antiemetic.
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• Hypersensitivity: idiosyncratic drug hypersensitivity to AZA is uncommon
and usually starts within the first few weeks of treatment. Symptoms
are often non-specific and flu-like with nausea, malaise, arthralgia.
Urticarial, maculopapular and vasculitic rashes may occur. In severe cases
hypotension and shock may occur with possible fatality. Treatment should
be discontinued if hypersensitivity is suspected. Any rechallenge should be
attempted in hospital with a reduced dose. Some patients may tolerate
6-MP as an alternative therapy.
• Hepatitis: mild abnormalities of transaminases (<2 times upper limit of
normal) are not uncommon and may settle with continued treatment.
Deteriorating or sustained elevations of LFTs require dose reduction
or discontinuation of therapy. Acute drug induced liver injury may be
hepatocellular (high transaminases) or cholestatic (high bilirubin and
alkaline phosphatase). The latter usually takes longer to resolve. A chronic
pattern of liver injury termed nodular regenerative hyperplasia has been
reported in transplant recipients and patients with IBD.
• Haematological: bone marrow suppression is one of the most serious
adverse effects and can be fatal. As measurement of baseline TPMT does
not identify all patients at risk of severe bone marrow suppression, it is
essential that all patients are carefully monitored by regular measurement
of FBC. Leukopenia is commonest, but anaemia or thrombocytopenia may
also occur. These may develop suddenly or slowly over several months. Mild
lymphopenia (0.5–1.0 × 109/L) is often observed and does not usually lead to
complications. Macrocytosis is also common and can be helpful to monitor
compliance. B12 and folate deficiency should be excluded.
There are no specific guidelines for dose reduction according to
haematological parameters. Mild reductions in haemoglobin, a leukocyte
count 3–4 ×109/L or platelet count of 70–100 ×109/L may be managed
by reducing the dose of AZA by 50% and further close monitoring. The
original dose can be resumed if values normalize, but treatment should be
discontinued if indices continue to fall.
• Malignancy: thiopurines have been in clinical use for several decades,
and there is evidence that they have a good safety record in terms of
carcinogenicity. The exception is non-melanoma skin cancer (NMSC), where
they increase the risk of photo-carcinogenesis. In transplant recipients, longterm use of AZA combined with other immunosuppressants raises the risk
of NMSC development more than 200-fold. AZA may carry a proportionally
higher risk than other immunosuppressants as the absorption spectrum of
6-TG peaks at 340 nm (within the ultraviolet A [UVA] spectrum). Irradiation
of 6-TG substituted DNA induces free radicals formation, which subsequently
causes irreparable DNA damage. In the short term this manifests as
increased UVA sensitivity; in the longer term, carcinogenesis. It is therefore
important that those treated with AZA are advised about sun protection,
self-examination and the need to report any suspicious skin lesions.
It remains controversial whether AZA treatment of dermatological
disease carries any increased risk of internal malignancy. Studies in transplant
recipients and those with IBD have shown increased rates of lymphoma
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(including hepatosplenic T-cell lymphoma), but these appear to relate to the
intensity of immunosuppression and underlying bowel disease, respectively.
For treatment periods of less than 1 year, there is no obvious risk for
dermatology patients. Those requiring longer-term therapy, can be advised
that any increase in risk appears small.
• Infection: AZA may increase the risk of infection even in the absence of
neutropenia. In practice, this does not appear to be a common clinical
problem among dermatology patients. However, patients taking AZA may
be susceptible to more severe infection with VZV. Non-immune individuals
may require VZ immunoglobulin or prophylactic aciclovir (acyclovir) if they
have significant exposure to chickenpox or herpes zoster.
• Pancreatitis has been reported in patients with underlying IBD.
++Use in special situations
Pregnancy
There is no conclusive evidence that thiopurines are teratogenic, but they
cross the placenta and are categorized as risk group D by the FDA (evidence of
fetal risk, which may be outweighed by maternal benefits in life-threatening/
serious disease), so their prescription in pregnant females requires careful
consideration. Human studies have shown that AZA does not affect sperm
quality or male fertility.
Lactation
Negligible amounts of AZA and its metabolites are present in breast milk, and
although the World Health Organization (WHO) has advised that the risks to
the infant outweigh any benefit, recent evidence does not support this.
Children
AZA is licensed for use in childhood and has been reported to be safe and
effective for severe atopic eczema. High doses may be needed (2.5–3.5 mg/kg)
to achieve remission. Long-term use needs careful consideration as the risk of
skin cancer increases with treatment duration, so photo-protection is essential
in this age group. Nausea and loss of appetite can be a problem in children,
and may be helped by taking medication with food in the evening.
Elderly
The elderly take more medication and are therefore are at increased risk of
drug interactions. They are also more susceptible to the adverse effects of AZA,
so lower dosages should be considered.
++Essential patient information
Patients should be informed of the reasons for treatment and whether the
drug is being used for a licensed indication or not. It should be explained that
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the onset of action is slow and that benefit may not appear until after 2–3
months’ treatment.
The dermatologist should ensure that patients clearly understand the need
for regular blood monitoring in order to minimize the risk of adverse effects
and are able to comply with this. Patients should be warned that they are at
increased risk of infection and should seek urgent medical attention if they
develop the following symptoms and signs:
• High fever/severe flu-like illness.
• Severe sore throat.
• Unexplained bruising or bleeding.
• Jaundice.
The increased risk of skin cancer should be discussed and patients given
practical information about sun protection and skin surveillance. In patients
requiring longer-term use, the possible increased risk of malignancy, especially
lymphoma should be discussed. In fertile females, advice should be given
regarding the possible risks of AZA in pregnancy.
With acknowledgements to Francisco A. Kerdel who reviewed this chapter
from the international perspective.
++Further reading
Fuggle NR, Bragoli W, Glover M, Martinez AE, Kinsler VA. The adverse effect
profile of oral azathioprine in pediatric atopic dermatitis and recommendations
for monitoring. J Am Acad Dermatol 2015;72:108–14.
Meggitt S, Anstey AV, Mohd Mustapha MF, Reynolds NJ, Wakelin S. British
Association of Dermatologists Guidelines for the Safe and Effective Prescribing
of Azathioprine. Br J Dermatol 2011;165:711–34.
Milsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication
effects on male fertility. Dermatol Ther 2013;26:337–46.
Patel AA, Langan SM, Batchelor JM. A randomized trial of methotrexate
vs. azathioprine for severe atopic eczema: a critical appraisal. Br J Dermatol
2012;166:701–4.
Patel AA, Swerlick RA, McCall CO. Azathioprine in dermatology: the past the
present and the future. J Am Acad Dermatol 2006;55:369–89.
Public Health England. Immunisation against infectious disease 2014;
accessed at:
https://www.gov.uk/government/collections/immunisation-against-infectiousdisease-the-green-book.
Schram ME, Borgonjen RJ, Bik CM, et al. Off label use of azathioprine in
dermatology: a systematic review. Arch Dermatol 2011;147:474–88.
Weidmann AK, Young HS. Azathioprine in the 21st century. CML-Dermatology
2011;16:61–7.
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Azole Antihelminths
Mahreen Ameen
++Classification & mode of action
The antihelminth drugs that are most commonly used in dermatology are
the two benzimidazole carbamates, albendazole, which was first approved in
1983, and mebendazole, which was introduced in 1972. These long-established
agents are used in both human and veterinary medicine. Tiabendazole
(thiabendazole) is no longer used systemically due to serious adverse effects
and its topical use is not advocated for treatment of cutaneous larva migrans
unless systemic therapy is contraindicated.
Both albendazole and mebendazole have broad-spectrum antihelminth
activity. They are most commonly prescribed for the treatment of nematode
infestations including roundworm, whipworm, threadworm and hookworm.
Albendazole and mebendazole have a number of mechanisms of action: they
act as vermicidals by causing selective degenerative alterations in the tegument
and intestinal cells of the worm, and by impairing cellular metabolism, thereby
leading to immobilization and death of the parasite.
Albendazole and mebendazole are poorly absorbed following ingestion,
and absorption is greatly enhanced if taken with food, especially a fatty meal.
Administration on an empty stomach is only appropriate when intraluminal
parasites are targeted. Both drugs undergo extensive first-pass metabolism in
the liver and metabolic activation and detoxification depend on cytochrome
P450 (CYP450) 2C and flavin mono-oxygenases. The oral bioavailability of
mebendazole is reported to be less than 20%, which is significantly less than
that of albendazole, and is a consequence of both poor absorption and rapid
first-pass metabolism.
++Indications & dermatological uses
Soil transmitted helminthiasis, which can parasitize the human gastrointestinal
(GI) tract is responsible for GI infection in millions of people worldwide.
In comparison, helminths are uncommon causes of skin diseases. Azole
antihelminth drugs are indicated as treatment for the following infestations:
Mebendazole: pinworm (threadworm), roundworm; whipworm and hook
worm. Licensed in Uk and FDA approved.
Albendazole: FDA approved for pork tapeworm (trichinosis) hydatid disease
caused by dog tapeworm (Echinococcus granulosus). Unlicensed in Uk.
The following are off label uses:
• Cutaneous larva migrans: this is the commonest helminth infestation of the
skin. It is characterized by a serpiginous rash and intense pruritus and is
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acquired from direct contact of the skin with soil or sand contaminated by
dog or cat hookworm, followed by percutaneous penetration and migration
of larvae within the epidermis.
• Gnathostomiasis: this is caused by the nematode Gnathostoma sp. and is
endemic in South Eastern Asian and Latin American countries. It is acquired
by consuming raw or insufficiently cooked meat or fish. Ingested larvae
cause cutaneous or, less frequently, visceral disorders.
• Trichinosis similarly is caused by eating undercooked pork or wild game
and is caused by the nematode Trichinella spiralis. It is endemic worldwide
and presents with facial oedema, particularly peri-orbitally, splinter
haemorrhages, fever and myalgia.
++Formulations/Presentation
Availability may differ according to country. Generally, albendazole is
the treatment of choice and mebendazole is usually only considered as a
second-line drug if albendazole is unavailable. Albendazole (200 mg and 400 mg)
and mebendazole (100 mg and 500 mg) are formulated as chewable tablets
and as an oral suspension (100 mg/5 mL).
++Dosages & suggested regimens
• Cutaneous larva migrans: albendazole 400 mg daily for 3–5 days. Ivermectin
is an alternative treatment (see Ivermectin).
• Gnathostomiasis: albendazole 400–800 mg daily for 21 days or ivermectin
0.2 mg/kg for 1–2 days. Cure rates are high and comparable for both drugs,
but the relapse rate may be higher with albendazole.
• Trichinosis: albendazole 400 mg bd for 8–14 days or mebendazole 200–400 mg
tds for 3 days.
++Baseline investigations & considerations/Monitoring
• None routinely required.
• FBC (CBC) and LFTs if underlying haematological or hepatic abnormalities
are suspected or when high dose/long-term benzimidazole therapy is
considered. Repeat during treatment if abnormal.
++Contraindications & cautions
• Albendazole and mebendazole are not recommended for use during
pregnancy and children under the age of 2 years.
• Hepatic impairment: both drugs must be used with caution in those with
hepatic impairment as they are metabolized in the liver and therefore
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severe liver disease may result in higher plasma levels of the parent drug
and metabolites. In cutaneous larva migrans alternative topical treatments
should be considered to avoid the risks associated with systemic therapy.
++Important drug interactions
• Cimetidine, an inihibitor of CYP450, may suppress the metabolism of the
benzimidazoles and increase the bioavailability of the active metabolites
of albendazole. Cimetidine does not appreciably raise serum mebendazole
leveld as these are low due to its poor systemic absorption.
• Antiepileptics: carbamazepine, phenobarbitone (phenobarbital) and
phenytoin can decrease the half-life of albendazole and mebendazole,
leading to a decrease in their serum concentration.
• Dexamethasone: can increase plasma levels of albendazole by up to 50%.
• Metronidazole: there have been reports of Stevens–Johnson syndrome
and toxic epidermal necrolysis occurring when high doses of either
metronidazole or mebendazole are given concomitantly.
++Adverse effects & their management
Albendazole and mebendazole have a similar adverse effect profile, with fewer
effects reported for mebendazole, probably because of very low absorption. In
spite of these, albendazole is considered a safe drug given the extensive clinical
experience using it over decades.
• Gastrointestinal adverse effects (>1%) include nausea, vomiting, diarrhoea
and abdominal pain. This is usually self-limiting and does not require special
treatment. However, children especially must be monitored for dehydration,
which may require active treatment if the individual is not able to tolerate
oral fluids.
• Headaches and dizziness are the next most commonly reported side-effects
and can be managed with simple analgesics.
• Hypersensitivity reactions including rash, pruritus and urticaria have been
reported less frequently. These are usually not severe and can be managed
with antihistamines and/or topical steroids. Telogen effluvium may also
occur.
• Hepatitis elevation of liver enzymes may occur (with a frequency of only
0.035%) but is usually self-limiting without serious sequelae. There is an
increased risk of this with long-term therapy. The detection of elevated
liver enzymes seldom necessitates discontinuation of drug therapy. Closer
monitoring is recommended in patients with underlying liver disease.
• There have been very rare reports of acute liver failure, bone marrow
suppression with agranulocytosis and aplastic anaemia.
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Azole Antihelminths
++Use in special situations
Pregnancy
Albendazole and mebendazole (both FDA Category C) are not recommended
in pregnancy because animal studies have found that they are teratogenic and
embryotoxic. Therefore, it is not recommended that they are administered
during pregnancy or in females thought to be pregnant. Females of childbearing
age should be advised to avoid conception during and for one month after
completion of treatment. However, clinical trials have also demonstrated
a lack of adverse birth outcomes after deworming pregnant females with
mebendazole. Therefore, pregnancy is not an absolute contraindication to
benzimidazoles but it is suggested that treatment should be avoided in the
first trimester of pregnancy.
Lactation
Low concentrations of albendazole and its active metabolite are detectable
in breast milk after a single dose of albendazole 400 mg. However, these low
levels are not considered to be harmful to the infant. Therefore, there is no
absolute contraindication to the use of albendazole in breastfeeding mothers.
There are very limited data on the presence of mebendazole in breast milk, but
given its low bioavailability it is unlikely to be significant.
Children
The benzimidazoles are generally not recommended in children under the age
of 2 years. However, clinical data suggest that the incidence of adverse effects
is likely to be the same in young children as in older children. Therefore, both
albendazole and mebendazole can be used from the age of 12 months if the
risks of not treating outweigh the risks of drug related adverse effects.
With acknowledgements to Garrett Coman who reviewed this chapter from an
international perspective.
++Further reading
Albanese G, Venturi C. Albendazole: a new drug for human parasitoses.
Dermatol Clin 2003;21(2):283–90.
Gyorkos TW, Larocque R, Casapia M, Gotuzzo E. Lack of risk of adverse
birth outcomes after deworming in pregnant women. Pediatr Infect Dis J
2006;25(9):791–4.
Montresor A, Awasthi S, Crompton DW. Use of benzimidazoles in children
younger than 24 months for the treatment of soil-transmitted helminthiasis.
Acta Trop 2003;86(2-3):223–32.
Van den Bossche H, Rochette F, Hörig C. Mebendazole and related antihelmintics.
Adv Pharmacol Chemother 1982;19:67–128.
Van den Enden E. Pharmacotherapy of helminth infection. Expert Opin
Pharmacother 2009;10(3):435–51.
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Ciclosporin
Murtaza Khan & John Berth-Jones
++Classification & mode of action
Ciclosporin (cyclosporine) is a lipophilic cyclic undecapeptide (11 amino acid
residues) with a molecular weight of 1202 daltons. It is the original calcineurin
inhibitor and was first isolated in 1970 from the soil fungus Tolypocladium
inflatum during a search for antifungal agents. The drug was found to have
immunosuppressive actions and its use revolutionized solid organ transplant
medicine. It was inadvertently found to be effective in the treatment of
psoriasis in 1979.
Ciclosporin exerts immunomodulatory effects mainly by preventing the
activation of T-lymphocytes which are implicated in the pathogenesis of
inflammatory skin disorders such as psoriasis and atopic dermatitis. It binds
to a cytoplasmic protein, cyclophilin, forming a complex that inhibits the
activity of calcineurin. In T cells calcineurin normally activates nuclear factor of
activated T cells (NFATc), which promotes the production of interleukin-2 (IL-2)
and numerous other cytokines that initiate the activation and proliferation of
T cells. In addition, the drug inhibits the release of histamine from mast cells
which may in part explain its usefulness in urticaria.
Gastrointestinal (GI) absorption varies according to food intake and gut
motility and plasma levels vary between individuals. This variation is reduced
by the use of microemulsion formulations. Ciclosporin is metabolized by
the cytochrome P450 (CYP450) enzyme system (predominantly CYP3A4 and
CYP3A5) in the liver and therefore has many potential drug interactions. Its
metabolites are predominantly eliminated in the bile so alteration in renal
function does not increase blood levels significantly.
++Indications & dermatological uses
Ciclosporin has been used for the treatment of inflammatory bowel disease,
nephrotic syndrome and rheumatoid arthritis. It is widely used in the prevention
of transplant rejection.
• The licensed dermatological indications in the UK for the use of ciclosporin
are severe psoriasis and severe atopic eczema.
Ciclosporin has been shown to greatly improve the quality of life in
patients with psoriasis in randomized controlled trials. It is effective in the
management of severe chronic plaque psoriasis, erythrodermic psoriasis and
pustular psoriasis. In addition, it improves joint disease in psoriatic arthritis.
In the USA, ciclosporin is approved for the treatment of adult patients with
severe or recalcitrant psoriasis. It leads to an approximate PASI 75 of 70% at 12
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Ciclosporin
weeks. Ciclosporin is widely used for the treatment of severe atopic dermatitis
(atopic eczema), although not FDA approved for this indication. The rapid
onset of action of ciclosporin is particularly useful for short-term control of
atopic dermatitis and it has been shown to be effective and well-tolerated in
children aged 2–16 years.
There are numerous reports of off-label uses of ciclosporin in dermatology,
including the following:
• Behçet’s disease.
• Chronic urticaria.
• Connective tissue diseases including scleroderma and dermatomyositis.
• Immunobullous disorders such as pemphigus and epidermolysis bullosa
acquisita.
• Lichen planus.
• Nodular prurigo (prurigo nodularis).
• Palmo–plantar pustulosis.
• Photodermatoses such as chronic actinic dermatitis and solar urticaria.
• Pyoderma gangrenosum.
• Toxic epidermal necrolysis.
++Formulations/Presentation
Differences may occur in the bioavailability of the various formulations and
brands of ciclosporin. For dermatological use, the modified microemulsion
forms of ciclosporin, Neoral or Gengraf (in the USA), are usually prescribed as
they offer better bioavailability than the non-modified form. Physicians should
specify the brand when prescribing and should not switch randomly between
brands.
Several branded formulations are available in the UK in the following forms:
• Capsules: 25 mg and 100 mg ciclosporin (Neoral, Gengraf, modified), 25 mg,
50 mg and 100 mg ciclosporin (Sandimmune, non-modified).
• Oral solution: sugar-free solution containing ciclosporin 100 mg/mL. This
may be mixed with orange or apple juice to improve the taste but not with
grapefruit juice. Avoid milk due to the unpleasant taste
• Sandimmune is also available in a concentrate for i/v infusion containing
ciclosporin 50 mg/mL.
++Dosages & suggested regimens
• Ciclosporin should be taken as two divided doses per day.
For psoriasis: for non-urgent cases, the recommended starting dose is
2.5–3.0 mg/kg/d, which can be titrated up to 5 mg/kg/d over 6–8 weeks.
For severe or urgent cases in which a rapid effect is required, treatment should
be initiated at 5 mg/kg/d. Improvement is usually apparent within 6 weeks
and the drug should be discontinued if there is an inadequate response after
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3 months of therapy. Once sufficient improvement is observed the dose should
be slowly reduced by 0.5–1 mg/kg/d to the lowest effective dose.
Treatment should be limited to intermittent short courses lasting 3–6 months,
which are usually sufficient for the control of most cases of psoriasis. However,
some patients with severe disease may require therapy for several years,
exceeding the limit of 1 year of continuous therapy recommended in the
FDA guidelines. In this situation the lowest effective dose should be used with
meticulous monitoring for side-effects. In obese patients, ideal bodyweight
should be used for dose calculation. Due to the risk of renal toxicity continuous
use of ciclosporin for more than 2 years is not recommended.
For atopic dermatitis: ciclosporin is licensed in the UK for short-term
treatment (usually up to 8 weeks). Although not FDA approved for this
indication, there are similar guidelines for its widespread use in the USA.
Ciclosporin is effective and well-tolerated in adults and is highly effective
and probably better tolerated in younger children. Ciclosporin can be used
at a starting dose of 5 mg/kg/d for the first 2–4 weeks, by which time a
clinical response is expected. Thereafter the dose is gradually tapered.
An alternative approach is to start with a lower dose (e.g. 2.5 mg/kg/d).
The use of ciclosporin for longer term, i.e. up to 12 months, for adults with
severe atopic dermatitis has been studied and shown to be generally safe and
effective.
++Baseline investigations & considerations
• BP should be monitored on at least two occasions, preferably 2 weeks apart.
• Physical examination to exclude infection and skin malignancy.
• Patients should be advised to follow recommended guidelines for cancer
screening, e.g. cervical smear, breast imaging, prostate cancer screening.
• Mean value of creatinine and eGFR should be recorded on 2 occasions 2
weeks apart.
• FBC (CBC), electrolytes, uric acid, LFTs and fasting lipids.
• Human immunodeficiency virus (HIV) test, if at risk of infection.
• During treatment with ciclosporin, vaccination may be less effective so the
use of live attenuated vaccines should be avoided.
++Monitoring
• BP should be monitored every 2 weeks for the first 2 months of treatment
and then monthly thereafter. BP should be maintained below 140/90 mmHg.
• Serum creatinine, eGFR and electrolytes should be measured every 2 weeks
for the first 2 months then every 2 months. A rise in creatinine of 25% above
baseline/ fall in eGFR by more than 25% (30% originally recommended),
even if within the normal range, should prompt dose reduction by 1mg/kg/
day and retesting after 2 weeks. If values do not improve, treatment should
be discontinued.
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• Fasting lipids should be measured as appropriate.
• Drug levels are not routinely monitored when ciclosporin is used at doses up
to 5 mg/kg/d. However, this can sometimes be useful, e.g. to assess suspected
non-adherence or drug interaction.
Special point
The serum creatinine is related to muscle mass. Patients with a low muscle mass
may have significant nephrotoxicity even though their serum creatinine remains
within the normal range, so baseline values should always be considered.
++Contraindications & cautions
Ciclosporin should generally be avoided in the following circumstances:
• Impaired renal function.
• Uncontrolled hypertension.
• Malignancy.
• Active infection.
• Concomitant ultraviolet (UV) B or psoralen and ultraviolet A (PUVA) therapy.
• Severe hepatic dysfunction.
• Immunodeficiency.
HIV-associated psoriasis is often severe and refractory to first-line therapies.
Ciclosporin may be used in special cases after careful evaluation and with the
expert advice of an infectious disease specialist. Close monitoring for adverse
effects is essential.
++Important drug interactions
Ciclosporin interacts with a large number of drugs and a database for drug
interactions such as the British National Formulary (BNF) should be consulted
for a full list. Some of the important interactions are listed below:
• Nephrotoxic drugs: other nephrotoxic drugs should be avoided as far as
possible, although the concomitant use of non-steroidal anti-inflammatory
drugs (NSAIDs) often occurs.
• Statins should generally not be co-administered with ciclosporin, as there
are metabolic interactions including inhibition of the metabolism of
statins by CYP450, increasing the risk of myopathy. However, some statins
(e.g. pravastatin) are not metabolized by CYP450 and the use of these
medications reduces the risk.
• CYP450 inducers and inhibitors: ciclosporin is metabolized by the hepatic
CYP450 system, primarily CYP3A4 and CYP3A5. This leads to a number
of potential drug interactions that may increase or decrease levels of
ciclosporin (Table 1).
• Grapefruit juice is also a CYP450 inhibitor and should be avoided while
taking ciclosporin. It also increases the absorption of ciclosporin from the
gut.
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TABLE 1 Cytochrome P450 (CYP450) inducers and inhibitors
CYP450 inducers (reduce ciclosporin
levels)
CYP450 inhibitors (increase ciclosporin
levels)
Rifampicin
Macrolide antibiotics (erythromycin,
clarithromycin)
Phenobarbitol
Ciprofloxacin
Carbamazepine
Fluoxetine
Phenytoin
Ketoconazole, itraconazole, fluconazole
St John’s wort
Omeprazole
Cimetidine
• Methotrexate and ciclosporin should not be co-prescribed if possible, as
each drug can reduce the elimination of the other.
• Aciclovir (acyclovir) and other antiviral drugs may increase the risk of
nephrotoxicity (see Antivirals for HerpesViruses).
• Antimalarials (chloroquine and hydroxychloroquine) increase the plasma
concentration of ciclosporin (see Antimalarials).
++Adverse effects & their management
• Hypertension: ciclosporin raises BP largely through a peripheral vascular
effect. If the systolic BP rises above 140 mmHg or diastolic BP rises above 90
mmHg, the BP should be checked again in 2 weeks. If it remains elevated
the dose of ciclosporin should be reduced by 25–50% or treatment with
an antihypertensive should be considered. Nifedipine is a useful drug as it
has a nephroprotective effect when used in combination with ciclosporin.
However, both drugs may cause gingival hyperplasia so monitor for this at
each visit.
• Nephrotoxicity: ciclosporin causes nephrotoxicity by mechanisms thought
to include renal vasoconstriction and hypoxia leading to the formation of
free radicals. The effects are related to dose and duration of treatment so
intermittent short courses are preferable. It also upregulates transforming
growth factor-beta (TGF-b) expression in juxtaglomerular cells, which
promotes renal fibrosis. A rise in creatinine of >25% requires dose reduction
(see monitoring). The creatinine level usually normalizes within 4–8 weeks
of cessation of the drug. Continued use can result in irreversible chronic
renal failure.
• Metabolic: hyperkalaemia, hypercalciuria and hypomagnesaemia (which
may cause muscle cramps). Hyperkalaemia is thought to be due to renal
tubular resistance to aldosterone. The risk is increased when administered
with potassium-sparing diuretics and aldosterone antagonists.
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Ciclosporin
• Hyperuricaemia may occur due to reduced urate clearance.
• Malignancy: patients treated with ciclosporin are at increased risk of nonmelanoma skin cancers, especially squamous cell carcinoma. This risk is
significantly increased in patients previously exposed to PUVA therapy.
Some studies have also reported an increased incidence of lymphoma.
Patients taking ciclosporin on a long-term basis should have examinations
of their skin, lymph nodes and abdomen every 6 months.
• Gingival hyperplasia: gum hypertrophy is a known side-effect of ciclosporin.
It is worsened by poor oral hygiene. If gingival hyperplasia develops patients
should be advised to see a dentist and in severe cases it may be necessary to
withdraw ciclosporin.
• Neurological: patients taking ciclosporin often report paraesthesia or
tremor, and seizure threshold may be lowered.
• Hepatotoxicity: liver dysfunction is sometimes seen in transplant patients
taking ciclosporin and is uncommon at the lower doses used in psoriasis. As
the drug is eliminated mainly in the bile, any liver disorder should prompt a
reduction in the dose or discontinuation of the drug.
• Hypertrichosis is common.
• Miscellaneous: sebaceous hyperplasia has mainly been reported in transplant
recipients. Fatigue, headache, flu-like symptoms, and GI disturbances occur
occasionally. Nausea and reflux may be helped by changing to a liquid
formulation.
++Use in special situations
Pregnancy (FDA Category C)
Ciclosporin has not been shown to be teratogenic in humans. There is
considerable experience of its use in mothers following organ transplantation
without any established serious hazard to the unborn child. There are some
reports of an association with premature labour. The manufacturer recommends
avoiding ciclosporin in pregnancy unless the benefits to the mother justify
potential risks to the fetus.
Lactation
Ciclosporin is excreted in breast milk and mothers taking the drug should not
breastfeed.
Children
Ciclosporin is not licensed in the UK for use in children less than 16 years, or
FDA approved for psoriasis patients less than 18 years. However, it has been
used in patients as young as 1 year of age in nephrotic syndrome, juvenile
dermatomyositis and organ transplantation without serious side-effects. As in
adults, the main risks are renal toxicity and hypertension.
Elderly
Elderly patients should be monitered with particular care for nephrotoxicity
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++Essential patient information
The important side-effects should be explained and supplemented with
written information. Patients should be advised to attend appointments for
clinical assessments and blood tests on a regular basis. Advice regarding the
avoidance of sunlight, interacting drugs and grapefruit juice should be given.
Patients should also be warned that any change in formulation should only be
done under physician supervision.
With acknowlwedgements to Rachael Morris-Jones and Anne Powles, authors
of this chapter in the 1st edition, and Eric Sorensen and Wilson Liao who
reviewed this chapter from an international perspective.
++Further reading
Berth-Jones J, Henderson CA, Munro CS, et al. Treatment of psoriasis with
intermittent short course cyclosporin (Neoral®). A multicentre study.
Br J Dermatol 1997;136:527–30.
Goshman L, Fish J, Roller K. Clinically significant cytochrome P450 drug
interactions. J Pharm Soc Wisconsin 1999:23–38.
Griffiths CE, Dubertret L, Ellis CN, et al. Ciclosporin in psoriasis clinical practice:
an international consensus statement. Br J Dermatol 2004;150(Suppl.67):11–23.
Harper JI, Ahmed I, Barclay G, et al. Cyclosporin for severe childhood atopic
dermatitis: short course versus continuous therapy. Br J Dermatol 2000;142:52–8.
Marsland AM, Griffiths CE. The macrolide immunosuppressants in dermatology:
mechanisms of action. Eur J Dermatol 2002;12:618–622.
Sarzi-Puttini P, Cazzola M, Panni B, et al. Long-term safety and efficacy of lowdose cyclosporin A in severe psoriatic arthritis. Rheumatol Int 2002;21:234–8.
Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J. Efficacy and safety of
systemic treatments for moderate-to-severe atopic dermatitis: a systematic
review. J Allergy Clin Immunol. 2014 Feb;133(2):429-38
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Clofazimine
Eglantine Lebas & Stephen L. Walker
++Classification & mode of action
Clofazimine is a riminophenazine dye and a cornerstone of the multidrug
therapy (MDT) of leprosy. It was first synthesized in 1954 as an antituberculous
drug but found to lack effectiveness, and was later marketed under the brand
‘Lamprene’ as a treatment for leprosy. Clofazimine is usually prescribed in
combination with rifampicin and dapsone. Since 1995, the World Health
Organization (WHO) has supplied MDT free of cost for leprosy sufferers in
endemic countries.
Clofazimine is highly lipophilic and tends to be deposited in fatty cells
and cells of the reticuloendothelial system. It has both antimycobacterial
and immunomodulatory properties. It has a slow bactericidal effect against
Mycobacterium leprae and preferentially binds to the guanine bases of bacterial
DNA, thereby inhibiting bacterial proliferation. It also increases activity of
bacterial phospholipase A2 leading to accumulation of lysophospholipids,
which inhibit cell wall integrity and bacterial proliferation. Clofazimine has
inhibitory actions on macrophages, neutrophils and T-lymphocyte proliferation,
blocking Kv1.3 channels in the latter, which are essential for memory T-cell
proliferation.
++Indications & dermatological uses
Clofazimine is indicated for the treatment of leprosy. It is only available on a
named patient basis in the UK and USA and is used as follows in leprosy:
• Multibacillary leprosy in combination with rifampicin and dapsone.
• Erythema nodosum leprosum (ENL).
Due to its immunosuppressive actions, clofazimine has been used in the
management of chronic discoid lupus erythematosus, granulomatous
cheilitis, chronic graft-versus-host disease, necrobiosis lipoidica, pyoderma
gangrenosum and other neutrophilic dermatoses such as Sweet’s syndrome.
Although not a first-line treatment for these diseases, it can be considered in
refractory cases.
It has been used to treat Mycobacterium avium complex infections in
patients with acquired immunodeficiency syndrome (AIDS) and has a role
in the management of multidrug resistant and extensively drug resistant
tuberculosis.
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++Formulations/Presentation
Oil-wax based capsules containing 50 mg and 100 mg clofazimine
(red-brown microcrystalline powder). Food increases the rate of absorption
and bioavailability.
++Dosages & recommended regimens
The WHO’s recommended dosage of clofazimine in MDT of multibacillary
leprosy is 300 mg once a month and 50 mg daily for the rest of the month for
at least 12 months. MDT is supplied in blister packs. Monotherapy should never
be used in the treatment of leprosy as it leads to drug resistance.
The WHO recommends that ENL reactions in lepromatous leprosy, which are
often recurrent and chronic in nature, are managed by experienced clinicians.
Clofazimine is used most commonly in persons with multibacillary leprosy who
are at risk of developing ENL reactions or who have recurrent or chronic ENL.
It may be given at higher doses of 300 mg a day for a maximum of 3 months
followed by 200 mg daily for 3–6 months. The maximum recommended
duration of high dose clofazimine is 12 months. For chronic inflammatory
dermatoses the usual effective dose is 100–200 mg/d.
++Baseline investigations & considerations/Monitoring
•
•
•
•
FBC (CBC).
Urea, electrolytes and creatinine.
LFTs.
Glucose.
++Contraindications & cautions
• Hypersensitivity to clofazimine.
• Soft contact lenses may be discoloured.
++Important drug interactions
Antimycobacterial drugs: clofazimine may reduce the absorption of rifampicin,
but this is not thought to be clinically relevant and they are often co-prescribed.
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++Adverse effects & their management
• Skin discolouration is a very common adverse effect of treatment
with clofazimine, occurring in approximately 80% of individuals. The
discolouration can range from pink to dark brown/black. It can be very
distressing for some patients, but slowly resolves after drug discontinuation.
In leprosy patients pigmentation tends to be most prominent on the face
and in lesions, and this can lead to further stigmatization and depression.
Discolouration of mucous membranes and most bodily fluids and secretions
also occurs. Hair may darken.
• Ichthyosis, particularly of the limbs and skin dryness with pruritus are also
common and resolve with cessation of the drug. Emollients can be helpful.
Other dermatological effects that have been reported rarely include
acneiform eruptions and photosensitivity.
• Gastrointestinal (GI) adverse effects are common affecting up to 50% of
patients, and include nausea, vomiting, abdominal pain and diarrhoea.
Rarely, a severe painful and sometimes fatal enteropathy can occur due to
the formation of clofazimine crystals in the tissues (sometimes referred to
as clofazimine crystal storing histiocytosis). Lymphadenopathy and splenic
infarction may occur. Clofazimine should be discontinued immediately if
patients develop severe GI symptoms. This may prevent unnecessary surgery.
• Other non-specific adverse effects include headache and fatigue. Blood
glucose levels may be elevated.
++Use in special situations
Pregnancy (FDA Category C)/Lactation
Clofazimine crosses the placenta and appears in breast milk in relatively large
amounts. Breast milk may turn pink and nursing infants of mothers taking
clofazimine have developed skin discolouration. The WHO recommends that
pregnant or breastfeeding females who have multibacillary leprosy should be
treated with standard MDT that includes clofazimine.
Children
Children with multibacillary leprosy aged 10–14 years are treated with a MDT
regimen including 150 mg clofazimine once a month and 50 mg on alternate
days of the month. Children under 10 years are treated with a monthly dose of
6 mg/kg/ then the equivalent of 1 mg/kg/d. The dosage interval of clofazimine
can be increased to achieve smaller daily doses.
Elderly
No special precautions are required.
With acknowledgemenst to Arjida Woolons and Martin M. Black, authors
of this chapter in the previous edition, and Toby Maurer who reviewed this
chapter from an international perspective.
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++Further reading
Arbiser JL, Maschella SL. Clofazimine. A review of its medical uses and
mechanism of action. J Am Acad Dermatol 1995;32:241–7.
Cholo MC, Steel HC, Fourie PB, Germishuizen WA, Anderson RJ. Clofazimine:
current status and future prospects. Antimicrob Chemother 2012;67(2):290–8.
Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N. Outcomes of clofazimine
for the treatment of drug-resistant tuberculosis: a systematic review and metaanalysis. J Antimicrob Chemother 2013;68:284–93.
Gurfinkel P, Pinna JC, Ramos-e-Silva M. Use of clofazimine in dermatology.
J Drugs Dermatol 2009;8:846–51.
Kumar B, Kaur S, Kaur I, Gangowar DN. More about clofazimine – 3 years
experience and review of literature. Indian J Lepr 1987;59(1):63–74.
WHO Guidelines for the management of severe erythema nodosum leprosum
(ENL) reactions, http://www.who.int/lep/research/WHOenlguide.pdf (accessed
27th October 2014).
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Colchicine
Malcolm W. Greaves
++Classification & mode of action
Colchicine is a pseudoalkaloid obtained from the meadow saffron (autumn
crocus Colchicum autumnale) and other Colchicum spp. that have been used
for medicinal purposes since the time of ancient Greece. It occurs as pale to
greenish yellow crystals and is irritating to skin. It is water soluble and oxidizes
rapidly on light exposure, so must be stored in the dark.
On ingestion, colchicine is rapidly absorbed (peak plasma levels 30–120
min after oral administration) and is mainly metabolized in the liver, although
10–20% is excreted unchanged in the urine.
Colchicine has anti-inflammatory actions, mainly through inhibition of
polymorphonuclear mobility, adhesion and chemotaxis. It also possesses
antimitotic activity since it prevents aggregation of the microtubular
cytoskeleton, thus inhibiting mitosis and causing metaphase arrest. It is
immunosuppressive due to reduced expression of cellular adhesion molecules
with resultant inhibition of T-cell activation. Cellular secretion of pro-collagen
is reduced, and collagenase production is increased. Colchicine also suppresses
activation of caspase 1 and release of interleukin (IL)-1b from stimulated
macrophages.
++Indications & dermatological uses
Colchicine is licensed only for use in gout and familial Mediterranean fever.
Dermatological uses, mainly supported by uncontrolled studies, include the
following:
• Recurrent aphthous stomatitis.
• Behçet’s disease.
• Neutrophilic dermatoses including Sweet’s disease and pyoderma
gangrenosum.
• Dermatitis herpetiformis (in patients intolerant of dapsone), epidermolysis
bullosa acquisita and linear IgA disease.
• Leukocytoclastic vasculitis, especially urticarial vasculitis.
• Scleroderma.
• Cutaneous amyloidosis.
Erythema nodosum and genital lesions in women have been shown to respond
but there is no clear effect on oral ulceration in Behçet’s disease. Except for
some forms of mucocutaneous Behçet’s disease, where colchicine has been
shown to be effective in double blind studies, it is not a first-line agent for any
of the above conditions.
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Colchicine
++Formulations/Presentation
Tablets contain 0.5 mg of colchicine. They should be stored in an airtight
container and protected from exposure to light.
++Dosages & suggested regimens
For dermatological conditions the the starting dose is 0.5mg daily, increasing
to 1–1.5 mg in divided (0.5 mg) doses, as tolerated. The dose tolerated by the
patient is usually dependent on gastrointestinal (GI) side-effects.
Special point
Colchicine has a narrow therapeutic window and is extremely toxic in overdose.
Specialist advice should be obtained promptly. There may be a delay of hours
to days before toxicity is apparent and as little as 6–7 mg of colchicine has
caused death. Acute toxicity manifests as cholera-like symptoms and signs
with dehydration, electrolyte disturbance, metabolic acidosis, renal failure and
shock. Convulsions, muscle paralysis, neuropathy and respiratory distress are
common. Chronic toxicity may cause leukopenia, aplastic anaemia, myopathy
and alopecia.
++Baseline investigations & considerations
• FBC (CBC).
• Urea, electrolytes and creatinine.
• LFTs.
++Monitoring
• FBC (CBC) and differential white cell count every month.
• LFTs and renal indices 3-monthly.
++Contraindications
• Haematological disease.
• Severe renal impairment or haemodialysis (colchicine cannot be removed by
dialysis or exchange transfusion).
++Cautions
• Elderly or debilitated patients may be especially susceptible to cumulative
toxicity, leading to GI, renal, hepatic, cardiac or haematological
complications.
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• Gastrointestinal hepatic or cardiac disease, due to the increased risk of
toxicity.
• Renal impairment or concurrent use of nephrotoxic drugs, due to increased
toxicity.
Do not use in patients with chronic kidney disease stage 5 (glomerular filtration
rate [GFR] <15 mL/min).
++Important drug interactions
• Macrolide antibiotics (erythromycin, clarithromycin and others) increase
the risk of colchicine toxicity, due to interactions with the cytochrome
P450 (CYP450) 3A4 microsomal enzyme system.
• Ciclosporin (cyclosporine) concentrations are increased by colchicine, with
an increased risk of nephrotoxicity and neuromuscular adverse effects.
• Vitamin B12 absorption may be impaired by colchicine resulting in
megaloblastic anaemia.
• Statins and fibrates may cause acute myopathy when given with colchicine.
Patients should be advised to report any muscular pain or weakness.
• Other potential interactions include drugs metabolized by CYP3A4 including
azole antifungals, antiviral drugs and cardiac medication.
++Adverse effects & their management
Colchicine is usually well-tolerated.
• Mild Gastrointestinal upset is common (vomiting, diarrhoea, abdominal
pain) and usually responds to dosage adjustment; failing this, the drug
should be withdrawn. Colchicine can less commonly cause malabsorption
syndrome affecting B12, fat, protein, actively transported sugars and
electrolytes. Other GI effects include stomatitis and paralytic ileus.
• Bone marrow suppression: agranulocytosis, thrombocytopenia and
aplastic anaemia can occur after prolonged treatment. Administration of
granulocyte colony stimulating factor (G-CSF) should be considered in such
cases.
• Myopathy and neuropathy: this occurs especially in patients with renal
impairment. The myopathy is proximal, with elevated serum creatinine
phosphokinase and the neuropathy is axonal. Myopathy recovers on
withdrawal of colchicine, but neurological recovery may be slow.
• Dermatological: these include urticaria and rarely Stevens–Johnson
syndrome, toxic epidermal necrolysis and alopecia universalis, and very
rarely porphyria cutanea tarda.
There have been isolated reports of bladder spasm, renal damage and
haematuria and hypothyroidism.
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++Use in special situations
Pregnancy (FDA Category C)
Colchicine is teratogenic in animals and there is some evidence of teratogenicity
or of fetal chromosomal abnormalities in humans, so it should be avoided in
pregnancy. There have been sporadic reports of oligospermia and azoospermia.
Lactation
Colchicine can be found in breast milk so it should be avoided during lactation.
Children
Safe use of colchicine has been reported in a small number of children. Colchicine
has been reported to be useful as an adjuvant treatment with systemic
corticosteroids in children with linear IgA disease. It is also an alternative to
dapsone in children who are glucose-6-phosphate dehydrogenase (G6PD)
deficient.
++Essential patient information
• Patients should be advised to reduce dosage of colchicine if weakness,
anorexia, nausea, vomiting or diarrhoea occurs.
• Patients should also be informed of the dangers of overdosage.
• Colchicine can adversely affect the fetus, so pregnancy should be avoided
during treatment.
With acknowlwedgements to Ruth Sabroe, author of this chapter in the 1st
edition.
++Further reading
Cocco G, Chu DC, Pandolfi S. Colchicine in clinical medicine. A guide for
internists. Eur J Med 2010;21:503–8.
Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RJ, Wessman G. Colchicine
alters the quantitiative and qualitative display of selectins on endothelial cells
and neutrophils. J Clin Invest 1995;96:994–1002.
Konda C, Rao AG. Colchicine in dermatology. Ind J Dermatol Venereol Leprol
2010;76:201–5.
Perico N, Osterman D, Bontempeill M, et al. Colchicine interferes with
L-selectin and leucocyte function-associated antigen-1 expression on human
T lymphocytes and inhibits T cell activation. J Am Soc Nephrol 1996;7:594–601.
Putterman C, Ben-Chetrit E, Caraco Y, Levy M. Colchicine intoxication: clinical
pharmacology, risk factors, features and management. Semin Arthritis Rheum
1991;21:143–55.
Sullivan TP, King LE, Boyd AS. Colchicine in dermatology. J Am Acad Dermatol
1998;39:993–9.
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Corticosteroids
Clive B. Archer
++Classification & mode of action
Synthetic corticosteroids (glucocorticoids, glucocorticosteroids, steroids)
are analogues of endogenous adrenal steroid hormones and are widely
used in dermatology. They have anti-inflammatory, immunosuppressive,
antiproliferative and vasoconstrictor actions. The effects of steroids are
mediated predominantly by binding to intracellular glucocorticoid receptors,
which then bind to specific DNA sequences that regulate gene transcription.
Corticosteroids also have non-genomic actions such as interactions with cellular
membranes and receptors. Corticosteroids thereby reduce inflammation via
several molecular mechanisms, suppressing the many inflammatory genes that
are activated in chronic inflammatory diseases and repressing the expression of
pro-inflammatory proteins.
Prednisolone and methylprednisolone are the steroids most commonly
used in medicine. The relatively high mineralocorticoid activity of cortisone
and hydrocortisone with consequent fluid retention makes them unsuitable
for long-term therapy.
After absorption corticosteroids bind to the carrier protein, transcortin
(cortisol binding globulin) and albumin. Transcortin levels are decreased in
liver disease, kidney disease, hypothyroidism and obesity. This may therefore
increase the level of free corticosteroid in these conditions. Liver disease also
results in decreased albumin levels and potentially increased steroid sideeffects. Steroids are metabolized by the liver to water-soluble metabolites that
are excreted by the kidneys.
The relative potencies and approximate equivalent doses of steroids
compared with hydrocortisone are shown in Table 1.
Prednisone is generally used instead of prednisolone in the USA. It is a pro-drug
that is converted to prednisolone in the liver. However, there is 20% less on
conversion and liver failure may impair conversion further. The onset of action
is also slower.
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TABLE 1 Relative potencies and approximate equivalent doses of corticosteroids
compared with hydrocortisone (reproduced with the permission of Guy’s
and St Thomas’ NHS Foundation Trust)
Drug
Hydrocortisone
(Cortisol)
Relative
glucocorticoid
(anti-inflammatory)
potency
Relative
mineralocorticoid
potency
Equivalent
antiinflammatory
dose* (mg)
1
1
100
Prednisolone
4
0.8
25
Methylprednisolone
5
0.5
20
Triamcinolone
5
0
20
Betamethasone
25
0
4
Dexamethasone
25
0
4
applies only to oral or i/v administration
*
++Indications & dermatological uses
The following corticosteroids are licensed for systemic use in the suppression of
inflammatory and allergic disorders:
• Betamethasone.
• Deflazacort.
• Dexamethasone.
• Methylprednisolone.
• Prednisolone.
• Triamcinolone.
Parenteral hydrocortisone is indicated for the treatment of anaphylactic shock
and angioedema.
Corticosteroids have been widely used in dermatology since the 1950s. Some of
the diseases for which they are commonly prescribed are as follows:
• Dermatitis: acute contact dermatitis, atopic dermatitis, chronic actinic
dermatitis, exfoliative dermatitis due to drugs.
• Connective tissue diseases: lupus erythematosus (all types), dermatomyositis,
mixed connective tissue disease, relapsing polychondritis, eosinophilic
fasciitis.
• Immunobullous diseases: pemphigus (all types), bullous pemphigoid,
cicatricial pemphigoid, pemphigoid gestationis, linear IgA disease,
epidermolysis bullosa aquisita.
• Vasculitis: hypersensitivity vasculitis, polyarteritis nodosa, Wegener’s
granulomatosis.
• Neutrophilic dermatoses: Sweet’s syndrome, pyoderma gangrenosum,
Behçet’s disease.
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• Other dermatoses: lichen planus, sarcoidosis, acute severe urticaria,
angioedema, Stevens–Johnson syndrome (but not toxic epidermal
necrolysis), large haemangiomas.
++Formulations/Presentation
Includes the following:
• Prednisolone: 1 mg, 2.5 mg, 5 mg and 25 mg tablets; 2.5 mg, 5 mg enteric
coated tablets (note decreased gastric absorption); 5 mg scored soluble
tablets.
• Betamethasone: 0.5 mg scored tablets; 0.5 mg scored soluble tablets.
• Triamcinolone: aqueous suspension for injection. As acetonide 10 mg/mL,
40 mg/mL; as hexacetonide 5 mg/mL, 20 mg/mL.
• Deflazacort: 1 mg, 6 mg, 30 mg tablets.
• Dexamethasone: 0.5 mg tablets.
• Methylprednisolone: 2 mg, 4 mg, 16 mg, 100 mg tablets; 40 mg, 125 mg,
500 mg, 1 g and 2 g powder for reconstitution with water (as sodium
succinate).
• Hydrocortisone: 100 mg/mL solution for injection (as sodium phosphate);
100 mg powder for reconstitution with water (as sodium succinate).
++Dosages & suggested regimens
Steroids given for immunosuppression are usually given as a single daily dose in
the morning to minimize adrenal suppression. Prednisolone has predominant
glucocorticoid activity and is used for most purposes. It has the advantage over
more potent steroids of allowing fine dose adjustment.
The starting dose of prednisolone varies according to the skin disease,
its severity and concurrent disorders such as hepatic impairment. The BNF
recommends a daily starting dose of 10–20 mg, up to 60 mg in severe disease.
In dermatological practice it may be necessary to use higher doses to gain
initial disease control, e.g. 60–100 mg prednisolone daily in pemphigus.
In children, a typical short course high dose regimen is 1–2 mg/kg/d for
3–5 days. If treatment is required for >7 days, the dose is usually reduced
gradually.
A high dose pulsed i/v regimen with 500 mg–1 g methylprednisolone daily
for 3 days may be faster acting and more effective than oral therapy, but these
advantages have yet to be fully validated and controlled prospective studies
are lacking.
For androgen excess syndromes, a unique regimen is indicated involving
night time suppressive therapy with low dose treatment (below physiological
levels) to suppress the early morning peak of adrenocorticotrophic hormone
(ACTH) that stimulates adrenal androgen production (see Antiandrogens).
The rate of drug withdrawal depends mostly on disease activity. Rapid
withdrawal may precipitate disease flares in some disorders. The maintenance
dose should be kept at the minimum required for the shortest length of time
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in order to minimize side-effects. Alternate day dosing may reduce adverse
effects by allowing time for the hypothalamic–pituitary–adrenal (HPA) axis to
recover.
Soluble formulations of prednisolone or betamethasone may be of
advantage in treating severe oral inflammatory disease (lichen planus,
pemphigus) as they can be held in the mouth before swallowing to obtain a
local anti-inflammatory effect.
Special point: Adrenal supression
The approximate physiological daily secretion of cortisol by the adrenal cortex
is 20 mg (equivalent to about 5 mg prednisolone daily). Short courses of high
dose prednisolone (2 weeks or less) do not require tapering as, although
suppressed, the HPA axis recovers promptly.
In patients on long-term prednisolone therapy, once a daily dose of 7.5 mg
has been reached, dose reduction should be slower to allow the HPA axis to
recover, e.g. 1–2.5 mg weekly.
Patients taking oral corticosteroids must continue systemic therapy during
periods of stress such as infection, trauma or surgery, either orally or by
injection. Extra steroids are needed for up to 3 days during periods of acute
illness to prevent an acute adrenal crisis. Patients who have been taking 5 mg
or more of prednisolone for more than 4 weeks are at risk of an adrenal crisis
during periods of high stress. Patients who have completed a short course of
treatment (3 weeks or less) within the previous week also require corticosteroid
replacement during acute stress.
++Baseline investigations & considerations
•
•
•
•
•
•
FBC (CBC).
Urea, electrolytes and creatinine.
LFTs.
Urinalysis for glucose and/or blood glucose – if at risk of diabetes.
Fasting lipid profile – if at risk of hyperlipidaemia.
Dual energy X-ray absorptiometry (DEXA) scan of lumbar spine and hips – if
long-term treatment is required.
• BP and weight.
• Growth chart for height and weight for children.
++Monitoring
After 1 month then every 2–3 months:
• BP.
• Urinalysis for glucose.
• Urea and electrolytes.
• DEXA scan after 6 months, 12 months then yearly.
• Consider ophthalmological review for cataracts and raised intraocular
pressure.
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++Contraindications
Systemic infection including latent tuberculosis (unless specific antimicrobial
therapy is given).
++Cautions
Corticosteroids should be used with caution in patients with the following preexisting disease which might be exacerbated:
• Diabetes mellitus.
• Hypertension or congestive heart failure.
• Glaucoma.
• Osteoporosis.
• Active peptic ulcer disease.
• Liver failure.
• Severe affective disorders/history of corticosteroid induced psychosis.
• Previous steroid myopathy.
• Kidney failure.
• Recent myocardial infarction (risk of cardiac rupture).
++Important drug interactions
• Antacids can reduce the absorbtion of prednisolone if given in high doses.
• Anticonvulsants: increased clearance of corticosteroids occurs with
carbamazepine, phenytoin and phenobarbitone.
• Antibiotics: increased clearance of corticosteroids occurs with rifampicin
and isoniazid.
• Ciclosporin (cyclosporine) increases the plasma concentration of
prednisolone.
• Coumarin anticoagulant efficacy may be enhanced by high dose
corticosteroids, so closer monitoring is required to avoid bleeding.
• The therapeutic effects of hypoglycaemic agents (including insulin),
antihypertensive therapy and diuretics are antagonized by corticosteroids.
• Corticosteroids may increase the risk of benign intracranial hypertension if
given with retinoids and tetracyclines.
++Adverse effects & their management
• Fluid and electrolyte imbalance (mineralocorticoid) effects are slight with
prednisolone, methylprednisolone and triamcinolone, and negligible
with betamethasone and dexamethasone. They include hypertension,
sodium and water retention and potassium loss. The risk of hypokalaemia
is increased when given with acetazolomide, loop diuretics and thiazide
diuretics.
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• Sudden death and life-threatening ventricular arrhythmias have been
associated with pulsed methylprednisolone therapy, possibly as a
consequence of rapid electrolyte shifts. All patients receiving such therapy
should preferably have cardiac monitoring and daily monitoring of
electrolytes.
• Glucocorticoid effects are the main problem associated with long-term
corticosteroid therapy. They include osteoporosis, diabetes mellitus and
Cushing’s syndrome.
• Corticosteroid myopathy typically affects the proximal muscles of the pelvic
then shoulder girdle. The patient should be asked if they have difficulty
rising from chairs and climbing stairs. Exercising and slow tapering of the
corticosteroid dose may help.
• Peptic ulcer disease: it is uncertain if corticosteroids increase the risk of peptic
ulcer disease, and if so, the effect is modest. There is clearer evidence that
they increase the risk of peptic ulceration when given with non-steroidal
anti-inflammatory drugs (NSAIDs). Treatment with proton pump inhibitor
or an H2-antagonist seems appropriate in patients with a history of peptic
ulcer disease or those who develop symptoms of gastritis. The potential
advantage of soluble or enteric coated preparations (with consequent
reduced gastric absorption) versus plain tablets to reduce the risk of peptic
ulceration remains uncertain. As corticosteroid therapy may mask the signs
of a perforated peptic ulcer or other visceral perforation, patients taking
these drugs who develop significant abdominal pain warrant urgent
specialist attention.
• Neuropsychiatric adverse effects include euphoria, irritability, anxiety, sleep
disturbance, cognitive impairment, depression, labile mood and suicidal
thoughts. Psychotic symptoms include mania, delusions and aggravation
of schizophrenia. Particular care is required when systemic corticosteroids
are given to patient with existing or a previous history of severe affective
disorders.
• Cardiovascular disease risk is increased in those on long-term corticosteroids.
Thrombophlebitis may also occur.
• Cutaneous adverse effects include atrophy, telangiectasia and striae.
Truncal acne may occur, but usually clears on corticosteroid withdrawal.
Corticosteroids impair fibroblast production of type 1 collagen and delay
wound healing.
• Ocular adverse effects include corneal thinning, glaucoma and posterior
subcapsular cataracts. Children are at increased risk of cataracts and
regular slit lamp examinations should be considered in those on long-term
treatment.
• Leukocytosis is a common finding due to reduced neutrophil margination.
• Infection: susceptibility is increased and infections may be more severe.
Clinical signs and symptoms of opportunistic infections and tuberculosis
may be suppressed. Chickenpox is of particular concern since this usually
minor illness may be fatal in immunosuppressed patients. Patients taking
corticosteroids without a definite history of chickenpox should avoid close
personal contact with chickenpox or herpes zoster and if exposed they
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should seek urgent medical attention. Passive immunization with varicella/
zoster immunoglobulin (VZIG) is required in non-immune patients who
are receiving systemic corticosteroids or who have used them within the
previous 3 months; this should ideally be given within 3 days of exposure. If
a diagnosis of chickenpox is confirmed, the illness warrants special care and
urgent treatment. Corticosteroids should not be stopped and the dose may
need to be increased. Similarly, patients should be advised to avoid contact
with measles, and if exposed without prior immunity, to seek prompt
medical attention for prophylaxis with normal immunoglobulin.
• Hypersensitivity reactions including anaphylaxis may occur rarely.
Special point: Osteoporosis
Bone loss is one of the most important adverse effects of corticosteroid therapy
even in low doses. Mechanisms include glucocorticoid inhibition of osteoblast
function and induction of osteoclast and osteocyte apoptosis. Bones with a
high trabecular content like vertebrae are most vulnerable. Asymptomatic
fractures may occur in up to 50% of patients receiving long-term glucocorticoid
therapy, and minimal trauma fractures occur at higher bone mineral density
(BMD) than with other primary or secondary causes of osteoporosis. The
greatest rate of bone loss occurs during the first 6–12 months of therapy, so
early preventative measures are important. A DEXA scan is the investigation of
choice to assess BMD.
A computerised tool, FRAX®, developed by The World Health Organization
(WHO) has recently become available online (www.shef.ac.uk/FRAX). It
provides an assessment of fracture risk in those aged 40 and over, taking
into account different osteoporosis risk fractures, including long-term (> 3
months) corticosteroid therapy and BMD, if available. Clinical risk factors for
the assessment of fracture probability are shown in Table 2. The World Health
Organization (WHO) classification of bone densitometry results is based on
comparison with the mean value for adults of the same age and sex:
• A normal value for BMD is within 1 standard deviation of the score
(T score 0 to −1).
• Osteopenia is defined as BMD value 1–2.5 standard deviations below the
mean (T score −1 to −2.5).
• Osteoporosis is diagnosed when the T score is −2.5 or lower.
Intervention to prevent osteoporosis should start as soon as corticosteroids
are prescribed. Lifestyle measures, such as exercise, stopping smoking and
restricting alcohol consumption, should be recommended for all patients.
Bisphosphonates are the agents of choice for treatment and prevention
of osteoporosis. They slow the rate of bone turnover. Alendronic acid or
risedronate sodium (given daily or once a week) are first-choice drugs and
disodium etidronate is an alternative (given in 2-week cycles every 13 weeks).
Calcium and vitamin D supplementation should be considered, especially
in patients whose dietary intake is unreliable. The recommended dosages are
1,000–1,500 mg calcium and 800 IU vitamin D daily. Milk, hard cheese and
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Corticosteroids
TABLE 2 Clinical risk factors used for the assessment of fracture probability.
•
•
•
•
Age
Sex
Low body mass index ≤ 19kg/m2)
Previous fragility fracture, particularly of the hip, wrist and spine
including morphometric vertebral fracture
• Parental history of hip fracture
• Current smoking
• Alcohol intake of three or more units daily
Secondary causes of osteoporosis including
• Rheumatoid arthritis
• Untreated hypogonadism in men and women
• Prolonged immobility
• Organ transplantation
• Type 1 diabetes
• Hyperthyroidism
• Gastrointestinal disease
• Chronic liver disease
• Chronic obstructive pulmonary disease
yoghurt are good sources of calcium. Vitamin D-rich foods include salmon,
mackerel and tuna. Ultraviolet exposure is another consideration, as individuals
who avoid the sun or expose little skin are at increased risk of vitamin D
deficiency.
Calcitonin also inhibits osteoclastic bone reabsorption and may be a more
suitable option in children and young adults.
Gonadal hormone replacement therapy with oestrogen supplements
for post-menopausal females reduces the risk of fractures. The oestrogen
receptor modulator raloxifene, which has potent agonist effects on bone and
antioestrogen effects on the uterus and breast, may be a good alternative.
Testosterone replacement should be considered in males with low testosterone
levels.
• Avascular necrosis (osteonecrosis) of bone may occur with high dose or
prolonged corticosteroid therapy. The femoral head is most commonly
affected and disease may occur bilaterally. Other sites include the femoral
condyles and head of humerus. Symptoms of pain or reduced movement at
one or more joints should prompt further investigation. Magnetic resonance
imaging (MRI) is more sensitive for diagnosing early avascular necrosis than
radiography. Specialist referral is warranted in suspected cases.
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Corticosteroids
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
All corticosteroids cross the placenta to a variable degree. Betamethasone
and dexamethasone cross the placenta readily, while 88% of prednisolone
is inactivated. In humans there is no convincing evidence that systemic
corticosteroids cause an increase in fetal abnormalities such as cleft lip. The
main risk when they are administered for prolonged periods or repeatedly
during pregnancy is intrauterine growth retardation. There is also a theoretical
risk of neonatal adrenal suppression, but this usually resolves spontaneously
after birth.
Menstrual irregularities may follow depot i/m corticosteroid therapy, but
are uncommon with oral therapy. Sperm counts may be decreased but this does
not usually impair fertility.
Lactation
Corticosteroids are excreted in small amounts in breast milk. However, doses of
up to 40 mg daily of prednisolone are unlikely to cause systemic effects in the
infant. Infants of mothers taking higher doses than this should be monitored
for signs of adrenal suppression.
Children
Long-term corticosteroids cause growth suppression in children. Full catch up
growth may not be attained after medication is discontinued. Normal growth
is achieved on 5 mg prednisolone per day for a child with 1 m2 surface area.
Alternate day dosing may reduce growth suppression but can have reduced
therapeutic effectiveness against the disease being treated.
++Essential patient information
The Medicines Control Agency has documented the recommended advice
that should be given to patients who are prescribed long-term systemic
corticosteroids (see below). It is important to tell patients prescribed systemic
corticosteroids (especially for >7 days) about their possible adverse effects and
of the actions they may need to take. It is also important to inform patients
about the benefits of treatment. Specifically, they should be advised:
• Not to stop taking corticosteroids suddenly.
• To see a doctor if they become unwell.
• Of the increased susceptibility to infections, especially chickenpox (see
above).
• Of the serious side-effects that may occur.
• To read and keep the patient information leaflet.
• Always to carry the Steroid Treatment Card and to show it to any health
professional involved in their treatment. Patients may also be advised to
wear a Medical Alert bracelet.
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(Reproduced with kind permission of the Medicines Control Agency)
With acknowledgements to Fiona Keane, the author of this chapter in the 1st
edition.
++Further reading
Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol
2011;163:29–43.
Committee on Safety of Medicines and Medicines Control Agency. Focus on
corticosteroids. Curr Prob Pharmacovigil 1998;24:5–10.
Compston J, Cooper A, Cooper C et al. Guidelines for the diagnosis and
manangement of osteoporosis in postmenopausal women and men from the
age of 50 years years in the UK. Maturitas 2009;62:105–108.
Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment.
Prepared by a working group in collaboration with the Royal College of
Physicians, the Bone and Tooth Society of Great Britain, and the National
Osteoporosis Society, London: Royal College of Physicians; 2002.
Mitra R. Adverse effects of corticosteroids on bone metabolism: a review. Phys
Med Rehab 2011;3:466–71.
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Cyclophosphamide
Olga Golberg & Karen Harman
++Classification & mode of action
Cyclophosphamide is an antineoplastic drug from the nitrogen mustard group of
alkylating agents, which also include melphalan and chlorambucil. The primary
mechanism of action is DNA cross-linking, by irreversibly binding an alkyl group
to the guanine base of DNA. This leads to the inhibition of DNA replication
and cell division. Cyclophosphamide causes immunosuppression by affecting
T-cell mediated and humoral immunity, mainly proliferating B-lymphocytes. It
is well absorbed after oral administration, with a bioavailability of greater than
75%. Cyclophosphamide is converted in the liver to active metabolites, such
as phosphoramide mustard and toxic compounds by specific cytochrome P450
(CYP450) isoenzymes. The half-life of the drug is 3–12 hours. Its metabolites are
excreted in the urine and have an irritant effect on the bladder mucosa.
++Indications & dermatological uses
The main use of cyclophosphamide is in combination with other agents in the
treatment of a wide range of lymphomas, leukaemias and solid tumours. It is
also used as an immunosuppressant in severe, refractory autoimmune disorders.
The only approved dermatological indication is in advanced mycosis fungoides;
all the other dermatological uses of cyclophosphamide are unlicensed. The
main uses in dermatology include:
• Immunobullous diseases: pemphigus (vulgaris, foliaceus), pemphigoid
(bullous, cicatricial).
• Vasculitides: refractory cutaneous vasculitis, polyarteritis nodosa,
antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (e.g.
Wegener’s granulomatosis), cryoglobulinaemic vasculitis, autoimmune
connective tissue disease associated vasculitis.
• Connective tissue diseases: systemic and cutaneous lupus erythematosus,
dermatomyositis, Behçet’s disease.
• Pyoderma gangrenosum.
++Formulations/Presentation
• Tablets contain 50 mg cyclophosphamide.
• Vials containing 500 mg of cyclophosphamide powder to reconstitute for
i/v injection and infusion. This may be used to prepare an elixir for oral use.
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++Dosages & suggested regimens
High doses and complex regimens are used in the treatment of malignant
diseases, before bone marrow transplantation and for severe autoimmune
disease. Dermatological diseases are usually managed with lower doses of
50–200 mg/d and seldom require more than 2.5 mg/kg/d. Cyclophosphamide is
commonly used in conjunction with systemic corticosteroids. Regimens vary from
daily oral administration to fortnightly or monthly pulses, or a combination of
these. Studies comparing pulsed i/v and daily oral cyclophosphamide therapies
in vasculitis suggest equal efficacy but a lower cumulative dosage and rate
of complications with pulsed regimens. However, the risk of relapse may be
higher. Large comparative trials of differing doses and regimens are lacking for
dermatological conditions.
A well-established pulse and oral regimen with corticosteroids reported by
Parischa and co-workers for the treatment of pemphigus is as follows:
• Days 1–3: 100 mg dexamethasone in 500 mL of 5% glucose as an i/v infusion
over 2 hours.
• Day 2: 500 mg cyclophosphamide added to the dexamethasone i/v infusion
(this constitutes one DCP [dexamethasone–cyclophosphamide pulse]).
• Days 4–28: oral cyclophosphamide 50 mg daily with conventional daily doses
of oral corticosteroids.
The cycle is repeated every 28 days until clinical remission is achieved and oral
steroids withdrawn (phase I: typically 3–4 months). DCPs continue in 28-day
cycles with 50 mg oral cyclophosphamide inbetween the pulses for a further
9 months (phase II), then oral cyclophosphamide 50 mg daily continued for
another 9 months (phase III). Treatment is then withdrawn (phase IV) and
patients followed-up for 10 years.
This protocol has been reported to induce long-term remission and possible
cure of pemphigus, indicating a disease modifying effect. It has also been used
for other dermatological diseases. Modifications to this regimen include using
i/v methylprednisolone (250–1000 mg on 3–5 days) instead of dexamethasone.
Another approach is to combine conventional daily oral corticosteroids with
monthly i/v cyclophosphamide pulses (15 mg/kg).
To induce remission in ANCA associated systemic vasculitis, cyclophosphamide
is often used as a first-line drug as follows:
• Oral cyclophosphamide 2 mg/kg/d (up to 200 mg/d) for 3 months then
continued or reduced to 1.5 mg/kg/d if remission achieved.
Or
• Cyclophosphamide i/v 15 mg/kg (max 1500 mg) given in 500 mL of 0.9%
saline or 5% dextrose over 1 hour. Requires pre-hydration with 1 L normal
saline and oral intake of 3 L/d for 3 days. The first 3 pulses are given 2
weekly, thereafter at 3-week intervals.
In this context, cyclophosphamide is discontinued after 3–6 months, and
alternative maintenance therapy established with azathioprine or methotrexate
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Cyclophosphamide
due to the risks of bladder and gonadal toxicity with prolonged therapy.
A reduced dose should be used in elderly patients and renal impairment (see
below).
Cyclophosphamide should be given early in the day and a high fluid intake
maintained throughout the day to encourage frequent bladder voiding.
Special point
Several rheumatological guidelines advise dose reduction in the elderly or those
with impaired renal function to reduce the risk of toxicity. Dose reductions for
continuous low dose oral cyclophosphamide:
• Age >60 years: reduce the dose by 25%.
• Age >75 years; reduce the dose by 50%.
Dose reductions for pulsed cyclophosphamide are shown in Table 1.
TABLE 1 Dose reductions for pulsed cyclophosphamide
Age (years)
Creatinine 150–300 µmol/L
Creatinine 300–500 µmol/L
<60
15 mg/kg/pulse
12.5 mg/kg/pulse
60–70
12.5 mg/kg/pulse
10 mg/kg/pulse
>70
10 mg/kg/pulse
7.5 mg/kg/pulse
++Contraindications
•
•
•
•
•
•
Previous urinary malignancy (urinary tract transitional cell carcinoma).
Haemorrhagic cystitis.
Bone marrow depression/severe leukopenia (see Figure 1A and B).
Pregnancy and lactation.
Hypersensitivity to cyclophosphamide.
Serious underlying infection.
++Cautions
•
•
•
•
•
•
Previous or concurrent mediastinal irradiation – risk of cardiotoxicity.
Hepatic impairment – reduce dose.
Hepatitis B and C virus.
Previous tuberculosis (TB) or risk of TB.
Renal impairment – reduce dose if creatinine >120 µmol/L (see above).
Elderly – reduce dose (see above).
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Cyclophosphamide
(A)
Management of leukopenia on oral cyclophosphamide therapy
WBC <4×109/L,
neutrophils <2×109/l*
Stop cyclophosphamide
temporarily. Restart
with a dose reduced
by 25 mg daily when
counts recover.
Monitor weekly
for 4 weeks
WBC < 1×109/L,
neutrophils <0.5×109/l
Stop cyclophosphamide
and restart at 50 mg
daily when counts
recover. Increase to
target dose weekly,
WBC permitting
Falling WBC
(<6 ×109/L and a fall of >2
×109/L over previous count)
Reduce dose by 25%
Prolonged leukopenia/neutropenia
WBC <4×109/L, neutrophils
<2×109/l* for >2 weeks
(B)
Management of leukopenia on pulsed cyclophosphamide therapy
Results on the day of the
pulse or previous day
If WBC <4 x 109/L,
neutrophil count
<2 x 109/L, postpone the
pulse until the counts
return to norrmal, while
checking FBC weekly.
Reduce the dose of the
next pulse by 25%
Nadir counts (days 10–14
after pulse)
WBC 1–2 x 109/L,
neutrophil nadir
0.5–1 x 109/L, reduce the
next dose by 40% of
previous dose (even if
counts normal just prior
tp the next pulse)
WBC 2–3 x 109/L,
neutrophil nadir
1–1.5 x 109/L, reduce the
next dose by 20% of
previous dose (even if
counts normal just prior
tp the next pulse)
FIGURE 1A,B Management of leukopenia on (A) oral and (B) pulsed cyclophosphamide therapy (data from Lapraik et al. 2007). *The lower value of the normal
neutrophil range may vary from centre to centre and should be checked against the
local laboratory reference range. WBC: white blood cell count.
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Cyclophosphamide
++Baseline investigations & considerations
• FBC (CBC) and differential white blood cell count to ensure normal
neutrophil count.
• LFTs and renal function.
• Urinalysis.
• Pregnancy test in females of childbearing age.
• Hepatitis B (HBV) and C (HCV) serology: HBV and HCV carriers are at risk of
a disease flare on immunosuppressant treatment. Non-immune individuals
should receive immunization against HBV. All patients seropositive for
HBV and HCV should be discussed with hepatology or infectious disease
specialists, as prophylactic antiviral treatment may be required.
• Varicella zoster (VZV) serology (if no history of chickenpox).
• HIV serology.
• TB risk should be assessed in all patients by clinical examination, history of
previous infection, chest radiograph (CXR) and, if appropriate, a tuberculin
test or IGRA as for patients being screened for antitumour necrosis factor
(TNF) therapy (see TNF Antagonists).
• Influenza and pneumococcal vaccinations are recommended and should
be administered at least 2 weeks before commencing cyclophosphamide.
Influenza vaccine should be given every year.
• Contraception: should be established in males and females prior to therapy
and continued for at least 3 months after treatment has ceased.
• Cervical screening should be up-to-date and a gynaecological review
undertaken in females with a history of cervical intraepithelial neoplasia
(CIN).
++Monitoring
Oral cyclophosphamide:
• FBC (CBC) weekly for the first month, 2 weekly for the next 2 months, then
monthly; consider decrease to every 3 months if stable after 3–6 months.
• Renal function, LFTs monthly for 3–6 months, then every 3 months if stable.
• Urinalysis monthly; after 3–6 months, every 3 months if stable.
• Urine cytology if haematuria or after cumulative dose of 50 g.
Pulsed cyclophosphamide:
• Check FBC and renal function prior to the first pulse of each cycle (on same
or preceding day); adjust dose if leukopenia/neutropenia (see Adverse
effects & their management and Figure 1).
• Nadir FBC should be checked between days 10–14 after pulsing (the nadir in
WBC usually occurs after 8–14 days with recovery after 18–25 days).
• If dose of cyclophosphamide or interval between pulses changes, nadir FBC
should be also checked (day 10).
• Renal function should be measured daily prior to infusions.
• Urinalysis monthly.
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Cyclophosphamide
Lifelong urinalysis every 6 months has been recommended following prolonged
treatment due to the risk of bladder cancer.
++Important drug interactions
• Diabetes therapy: cyclophosphamide may potentiate the hypoglycaemic
effects of sulphonylurea drugs and may alter glycaemic control.
• Allopurinol potentiates the bone marrow toxicity of cyclophosphamide.
• Barbiturates and clozapine can increase the risk of agranulocytosis.
• Digoxin absorption may be reduced by cyclophosphamide.
• Itraconazole and fluconazole may increase the risk of adverse effects with
cyclophosphamide.
• General anaesthesia – alert anaesthetist if cyclophosphamide has been used
within 10 days (as it enhances effects of suxamethonium).
• Live vaccinations are contraindicated during and for 3 months after
cyclophosphamide therapy.
++Adverse effects & their management
Alkylating agents are potent immunosuppressives. Their use is reserved for
severe disease because of concerns about serious side-effects.
• Haematological: leukopenia is dose related and can be used as a dosage
guide during treatment (Figure 1). Following a single dose, spontaneous
recovery usually occurs within 21 days. Anaemia and thrombocytopenia may
occur.
• Bladder toxicity and haemorrhagic cystitis have been attributed to a toxic
metabolite, acrolein, and appear to be related to the cumulative dose of
cyclophosphamide. Reactivation of a human BK polyoma virus may also play
a role. Haemorrhagic cystitis is associated with an increased risk of bladder
cancer (see below). Urine microscopy should be performed regularly
to detect early problems. Microscopic non-glomerular haematuria is a
significant risk factor for the development of bladder cancer. If five or more
red blood cells/high power field appear in the urine, cyclophosphamide
should be discontinued. Haematuria often resolves after a few days but if it
persists or is macroscopic, urology referral is indicated. Vigorous hydration
before and throughout therapy reduces the risk of haemorrhagic cystitis
– the aim is for a minimal urine output of 100 mL/h (2–3 L/d). Long-term
sequelae of this cystitis are bladder fibrosis and contracture. Mesna protects
the urinary epithelium by reacting with the toxic metabolite acrolein. It
should be considered in patients treated with i/v cyclophosphamide and
is used routinely in those who receive high dose treatment or have had
previous urothelial toxicity. Mesna can be given orally or i/v. When used
with pulsed i/v cyclophosphamide, the oral dose of mesna should be 40% of
the cyclophosphamide dosage in mg, given 2 hours prior to the pulse and
repeated 2 and 6 hours after the pulse of cyclophosphamide. The dose of
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Cyclophosphamide
•
•
•
•
•
•
•
•
•
i/v mesna should be 20% of the cyclophosphamide dosage in mg and given
with the pulse and then at 2 and 6 hours.
Malignancy: cyclophosphamide is specifically associated with an increased
risk of bladder cancer. Studies suggest the risk is dose related, especially
with cumulative doses exceeding 36 g. The risk of acute leukaemia, nonmelanoma skin cancer and other solid tumours may also be increased. These
can develop several years after treatment is discontinued.
Infection: risk is related to the severity and duration of drug induced
leukopenia. A WBC nadir ≤3 × 109/L has been associated with severe and
fatal infections in patients on cyclophosphamide therapy. Opportunistic
infections such as Pneumocystis jiroveci (carinii) infection may occur and
prophylactic antibiotic therapy may be indicated. The risk of infection is
greater in the elderly and those receiving simultaneous treatment with high
dose steroids.
Chickenpox or shingles contact in non-immune patients may lead to severe
infection, and VZV immunoglobulin should be considered.
Gastrointestinal: nausea, vomiting and anorexia are common and
dose related complications of cyclophosphomide therapy. They can be
managed with dose reduction and effective antiemetic medications, e.g.
i/v ondansetron before pulse therapy. Abdominal pain, diarrhoea and oral
mucositis may occur. Haemorrhagic colitis and hepatotoxicity are rare.
Dermatological: alopecia (anagen effluvium) occurs in 5–30% of patients
and is dose dependent. Hair regrowth occurs in most patients even with
continued treatment. Diffuse hyperpigmentation, especially of palmoplantar
skin and nail pigmentation may occur. Severe cutaneous adverse drug
reactions (including Stevens–Johnson syndrome/toxic epidermal necrolysis)
have been reported.
Cardiac and pulmonary: pulmonary fibrosis, interstitial pneumonitis
and cardiomyopathy are rare and associated with high doses of
cyclophosphamide used in the treatment of malignancy. The drug should be
discontinued if cardiac or pulmonary toxicity is suspected.
Hypersensitivity to cyclophosphamide may rarely occur, including
anaphylaxis. Possible cross-reactivity with other alkylating agents has been
reported.
Infertility: cyclophosphamide interferes with spermatogenesis and
oogenesis. Amenorrhoea, azoospermia and irreversaible sterility may
occur with prolonged therapy. Risk factors for cyclophosphamide induced
infertility include: age >30 years, long-term therapy, cumulative dose >10 g.
Expert advice should be sought for patients of reproductive age to discuss
the option of sperm or oocyte banking.
Minor adverse effects have been observed with pulsed i/v cyclophosphamide
and some are thought to be specific to this method of administration. These
include facial flushing, palpitations and hiccups occurred during i/v infusion,
whereas malaise, headache and taste alteration developed soon after DCP.
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++Use in special situations
Pregnancy (FDA Category D)
Cyclophosphamide is a known teratogen and should not be used in pregnancy except in life-threatening situations. Pre-natal exposure in the first
trimester has been associated with absent digits, abnormal facies, cleft palate
and hernias. Pregnancy should be avoided for at least 3 months after cyclophosphamide treatment in females and males.
Lactation
Cyclophosphamide is contraindicated in lactation as large quantities of active
metabolites are excreted in milk. Breastfeeding should not commence for 36
hours after stopping treatment.
Children
Cyclophosphamide is not recommended for treatment of skin disease in
children as it may cause irreversible loss of fertility.
++Essential patient information
Patients should be informed of the reasons for treatment, possible side-effects
and the need for regular blood monitoring. They should be specifically advised:
• To take cyclophosphamide in the morning and ensure good hydration (2–3
L of fluid a day) and frequent bladder voiding.
• To seek immediate medical help if they develop symptoms such as sore
throat, fever, easy bruising/bleeding, pallor, shortness of breath and cough.
• To use effective contraception during and for at least 3 months after
treatment.
• About the risk of infertility.
• To report any contact with VZV if non-immune.
• To ensure sun protection.
With acknowledgements to Harvey Smith and Martin Black, authors of this
chapter in the 1st edition, and Robert A. Brodsky who reviewed it from an
international perspective.
++Further reading
Bhat R, Sharma VK, Ramam M, et al. Cyclophosphamide pulses with oral
prednisolone in the treatment of pemphigus: a pilot study. Dermatol Online J
2005 Dec 1;11(3):4.
Cummins D, Mimouni D, Anhalt G. Oral cyclophosphamide for treatment of
pemphigus vulgaris and foliaceus. J Am Acad Dermatol 2003;49:276–80.
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Cyclophosphamide
Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden
anniversary. Nat Rev Clin Oncol 2009;11:638–47.
Faurschou M, Mellemkjaer L, Voss A, Keller KK, Hansen IT, Baslund B. Prolonged
risk of specific malignancies following cyclophosphamide therapy among
patients with granulomatosis with polyangiitis. Rheumatology 2014; Sept
17.pii:keu372. (Epub ahead of print.)
Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide
for induction of remission in ANCA-associated vasculitis: long-term follow-up.
Ann Rheum Dis 2012;71:955–60.
Lapraik C, Watts R, Bacon P, et al. BSR and BHPR guidelines for the management
of adults with ANCA associated vasculitis. Rheumatology 2007;46:1–11.
Pasricha JS, Poonam. Current regimen of pulse therapy for pemphigus: minor
modifications, improved results. Ind J Dermatol Venereol Leprol 2008;74:217–
21.
Saha M, Powell A-M, Bhogal B, et al. Pulsed intravenous cyclophosphamide
and methylprednisolone therapy in refractory pemphigus. Br J Dermatol
2010;162(4):790–7.
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Dapsone
Catherine Borysiewicz & Jonathan Leonard
++Classification & mode of action
Dapsone (4’,4’-diaminodiphenyl sulphone) was first introduced in the 1940s for
treatment of leprosy and remains an important therapy against Mycobacterium
leprae. It is structurally related to the sulfonamides (Figure 1) and shares
their antimicrobial action, i.e. impairing microbial synthesis of folate from
para-aminobenzoic acid (PABA) by competitive inhibition of the enzyme
dihydropteroate synthesase.
O
S
H2N
NH2
O
FIGURE 1 Chemical structure of dapsone.
Dapsone also has anti-inflammatory actions that account for much of its use
in dermatological diseases. The mechanism of this action is unclear but thought
to be due to inhibition of neutrophil function (chemotaxis and myeloperoxidase
activity) and release of inflammatory mediators. It may also have a local
anti-inflammatory effect. Dapsone inhibits the signal transduction cascade
common to chemotactic stimuli, suppressing neutrophil recruitment and local
production of toxic products.
Dapsone is readily absorbed with good bioavailability (>85%) and a
relatively long half-life (14–18 hours) allows once daily dosing. It is distributed
across all body organs and crosses the blood–brain barrier and placenta.
Dapsone is metabolized in the liver through a combination of hydroxylation
(cytochrome P450 [CYP450] dependent) into hydroxylamines which are toxic
and implicated in the haematological side-effects of the drug, and acetylation
(N-acetyl transferase dependent) into mono-acetyl dapsone which is non-toxic.
These products are then conjugated and excreted through the urine (Figure 2).
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Dapsone
Dapsone
Cytochrome
P450
N-acetyltransferase
Hydroxylation
Acetylation
N-hydroxy-dapsone
N-acetyl-dapsone
Toxic
Non-toxic
Conjugation
Urinary excretion
FIGURE 2 Metabolism of dapsone.
++Indications & dermatological uses
Dapsone is licensed for the treatment of leprosy and dermatitis herpetiformis
and Pneumocystis jiroveci (carinii) pneumonia prophylaxis in immunodeficient
subjects (especially acquired immunodeficiency syndrome [AIDS]). It is also of
benefit in a number of dermatoses characterized by neutrophilic infiltrates:
• Immunobullous dermatoses – linear IgA disease, chronic bullous dermatosis
of childhood, bullous pemphigoid and cicatricial pemphigoid.
• Neutrophilic dermatoses – erythema elevatum diutinum, Sweet’s syndrome,
subcorneal pustular dermatosis, leukocytoclastic vasculitis, pyoderma
gangrenosum and delayed pressure urticaria.
• Other inflammatory dermatoses including acne and rosacea, Behçet’s
disease, relapsing polychondritis and granuloma faciale.
• Severe, necrotic brown recluse spider bites.
++Formulations/Presentation
Dapsone is available as white scored 50 mg and 100 mg tablets.
++Dosages & suggested regimens
The World Health Organization (WHO) recommended dose for leprosy is
1–2 mg/kg/d.
• Multibacillary leprosy: regimens combining 3 drugs are recommended to
avoid development of resistant strains, using dapsone with rifampicin and
clofazimine for at least 2 years.
• Paucibacillary leprosy: combined with rifampicin for 6 months.
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Dapsone
For most dermatological conditions an initial dose of 50 mg daily should be
given for the first week to ensure there is no immediate adverse effect and then
adjusted according to the clinical response. The minimum drug requirement
for the majority of conditions lies between 1–2 mg/kg/d. In practice the dose
is usually increased by weekly 50 mg increments to achieve control of the
symptoms. The clinical response in dermatitis herpetiformis (DH) is prompt
and skin lesions start to resolve within 48 hours. However, some patients with
DH are resistant to dapsone and require higher doses. The maximum dosage
should not exceed 300 mg/d. If side-effects are not tolerated, then additional
use of sulfamethoxypyridazine or sulfapyridine should be considered to limit
the dose of dapsone and reduce dose related adverse effects.
The rash of DH is gluten dependent and the mainstay of therapy in the
long term is a strict gluten free diet (GFD). Patients who adhere to a strict GFD
are slowly able to reduce their minimum dapsone requirement and eventually
wean off dapsone altogether though it takes 2 years on average for the rash
to be controlled by GFD alone. Dapsone has no effect on the associated gluten
sensitive enteropathy.
++Baseline investigations & considerations
•
•
•
•
FBC (CBC) and reticulocyte count.
Urea, electrolytes and creatinine.
LFTs.
Glucose-6-phosphate dehydrogenase level (G6PD) in patients from ethnic
groups at risk of deficiency (see below).
• Assess patients for any medical condition (e.g. cardiorespiratory) that might
be exacerbated by a minor reduction in haemoglobin level.
• Urinalysis.
++Monitoring
• FBC, reticulocytes, urea and electrolytes, LFTs weekly for first month, then
monthly for 2 months then every 3–6 months if no increase in dosage.
• Urinalysis every 3 months.
• Measure methaemoglobin levels if patients are symptomatic.
• Urgent FBC if patients develop symptoms suggesting agranulocytosis.
Special point
G6PD deficiency is the most common disease producing enzyme deficiency
worldwide. It is an X-linked inherited disorder and most commonly affects
persons of African, Asian, Mediterranean or Middle-Eastern descent. Prevalence
of the deficiency is correlated with the geographic distribution of malaria, and
it is thought that the defect may confer some protection against this infection.
Sporadic gene mutations may affect all populations, and different mutations
result in different levels of enzyme deficiency, and disease manifestations.
Some people with G6PD deficiency are asymptomatic.
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Dapsone
G6PD catalyses the reduction of NADP to NADPH via the pentose phosphate
pathway, which is the only method of NADPH generation in erythrocytes
(Figure 3). They are therefore more susceptible to oxidative stress in the context
of infection and certain drugs and dietary triggers. Deficiency of G6PD greatly
increases this vulnerability and can lead to neonatal hyperbilirubinaemia and
acute or chronic haemolysis.
++Contraindications
•
•
•
•
•
•
Dapsone hypersensitivity.
Previous adverse reaction to sulfonamides.
Acute porphyria.
Severe ischaemic heart disease or pulmonary disease.
Severe anaemia – treat before starting dapsone.
Severe G6PD deficiency.
++Cautions
• Cardiac, peripheral vascular and pulmonary disease – particularly in
the elderly who may not tolerate minor reductions in haemoglobin
concentration.
• Other conditions predisposing to haemolysis.
• Dapsone can artifactually lower glycosylated haemoglobin levels in patients
with Type II diabetes and impair disease monitoring.
• Dapsone can be used with great caution at low dose and with close
monitoring in those with mild degrees of G6PD deficiency.
++Important drug interactions
• Probenecid: reduces urinary excretion of dapsone increasing plasma
concentration.
• Rifampicin: induces dapsone metabolism and enhances urinary excretion.
• Cimetidine: inhibits formation of toxic hydroxylamine metabolites and
increases the therapeutic/toxic ratio.
• Trimethoprim: decreases renal clearance of dapsone and increases the risk
of toxicity.
++Adverse effects & their management
• Haemolysis and haemolytic anaemia are dose related and due to reduced
erythrocyte survival. Mild haemolysis with a drop in haemoglobin of 1–2
g/dL (10–20 g/L) occurs in most patients at a standard therapeutic dose.
Hydroxylated metabolites of dapsone cause oxidation of glutathione, which
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Dapsone
in its reduced state plays an important role in maintaining erythrocyte
cell membrane integrity. Underlying G6PD deficiency impairs the ability
to maintain adequate reserves of reduced glutathione and therefore
predisposes individuals to severe haemolysis (see above).
• Methaemoglobinaemia is caused by the reaction of hydroxylated
metabolites of dapsone with oxyhaemoglobin (containing Fe2+) in
the presence of oxygen, leading to formation of a ferric compound
(Fe3+) that has reduced capacity for oxygen transport. Raised levels
of methaemoglobin can lead to symptoms of headache, shortness of
breath and lethargy and a bluish discolouration to lips and fingertips.
Methaemoglobin normally undergoes reduction by a NADPH dependent
enzyme methaemoglobin reductase and there is an adaptive increase
with time. Patients with a deficiency of the enzyme are more susceptible.
Methaemoglobinaemia does not need treatment unless patients are
symptomatic – if the level is >20% then dapsone should be discontinued;
at a level >30% additional measures can be taken. Cimetidine can reduce
methaemoglobin levels by inhibition of CYP450, which reduces synthesis
of the toxic hydroxylated metabolites (Figure 2). It can be prescribed at
a dose of 400 mg tds for mild methaemoglobinaemia. More severe cases
may require treatment with oxygen and i/v methylene blue 1% solution to
restore the iron in haemoglobin to its reduced oxygen carrying state.
G6PD
Glucose-6-phosphate
6-phosphogluconate
NAPD
NADPH
Glutathione
reductase
Oxidized glutathione
Reduced glutathione
FIGURE 3 Glutathione maintenance in erythrocytes.
• Agranulocytosis is a rare side-effect occurring in about 1:10,000 prescriptions
and due to a direct toxic effect of hydroxylated metabolites. It is usually
gradual in onset occurring within 2–16 weeks of starting therapy, but may
be sudden. It may also arise late in the course of treatment. A significant
drop in neutrophil count can present with fever, mouth ulcers and sore
throat. It may be accompanied by thrombocytopenia. Regular monitoring
of the blood count is therefore mandatory.
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Dapsone
• Sulfhaemoglobinaemia arises from direct combination of dapsone with
haemoglobin. It is rarely of clinical relevance.
• Dapsone hypersensitivity syndrome is a serious side-effect and usually takes
the form of DRESS (drug reaction [or rash] with eosinophilia and systemic
symptoms) type reaction. It is estimated to occur in approximately 1% of
patients. The onset is usually within 4–6 weeks of starting therapy, but may
be delayed up to 6 months. Patients present with fever, a morbilliform rash
that progresses to exfoliative dermatitis, lymphadenopathy, hepatitis with
elevated liver enzymes, peripheral eosinophilia and atypical lymphocytes. If
not recognized, the condition deteriorates and there is a significant risk of
death. The drug should be withdrawn immediately.
• Severe cutaneous reactions including toxic epidermal necrolysis and
Stevens–Johnson syndrome have also been reported.
• Gastrointestinal adverse effects such as anorexia, nausea and vomiting may
occur and can limit patients’ ability to tolerate and continue treatment.
Hepatitis, jaundice, cholestasis and abnormal LFTs may occur.
• Peripheral motor and sensory neuropathies have been reported rarely.
They are dose related and caused by axonal damage. Headache, insomnia,
malaise and rarely, psychoses have been reported.
• Renal adverse effects include proteinuria and, very rarely, nephrotic
syndrome.
++Use in special situations
Pre-conception
Animal studies have shown that dapsone can reduce the number of sperm
and their motility, potentially reducing male fertility though there is no clear
evidence for this in humans.
Pregnancy (FDA Category C)
Dapsone can cross the placenta and should be avoided in pregnancy if possible.
It has however, been used safely with no evidence of teratogenicity since its
introduction in 1947. Folic acid 5 mg daily should be given to females who are
pregnant. The greatest risk is in the last trimester when it may lead to neonatal
haemolysis and methaemoglobinaemia.
Lactation
Dapsone is secreted in breast milk and absorbed by the infant, giving rise to
mild haemolytic anaemia. The risk to the infant is considered small unless it has
G6PD deficiency.
Children
Dapsone has been used safely in infants and children at doses of 1–2 mg/kg/d.
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++Essential patient information
Patients should be advised of the need to attend for regular monitoring and to
seek urgent medical attention if affected by the following:
• Sore throat, mouth ulcers, purpura, bleeding – may indicate agranulocytosis/
bone marrow suppression.
• Shortness of breath, angina, jaundice – may indicate significant haemolysis.
With acknowledgements to Arjida Woolons and Martin M. Black, authors of
this chapter in the 1st edition.
++Further reading
Agarwalla A, Agrawal S. Dapsone hypersensitivity syndrome: a clinicalepidemiological review. J Dermatol 2005;32:883–9.
Frank JE. Diagnosis and management of G6PD deficiency. Am Fam
Phys 2005 Oct 1;72(7):1277–82.
Paniker U, Levine N. Dapsone and sulfapyridine. Dermatol Clin 2001;19:79–86.
Wright RO, Lewander WJ, Wood AD. Methemoglobinaemia: etiology,
pharmacology and clinical management. Ann Emerg Med 1999;34:646–56.
Piette EW, Werth VP. Dapsone in the management of autoimmune bullous
diseases. Immunol Allergy Clin North Am 2012;32(2):317–22.
Wolverton SE, Remlinger K. Suggested guidelines for patient monitoring
hepatic and haematological toxicity attributable to systemic dermatologic
drugs. Dermatol Clin 2007;25(2):195–205.
Wozel VE. Innovative use of dapsone. Dermatol Clin 2010;28(3):599–610.
Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update.
J Am Acad Dermatol 2001;45:420–34.
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Fumaric Acid Esters
Silja Domm, Kristian Reich & Ulrich Mrowietz
++Classification & mode of action
Fumaric acid esters (FAE) were first reported as an effective treatment
for psoriasis by the German chemist, Schweckendiek, in 1959. A mixture
of dimethylfumarate (DMF) and three salts of ethyl hydrogenfumarate
(Fumaderm®, Fumaderm® initial) was approved for the treatment of psoriasis
in Germany in 1994, where it remains a first-line systemic therapy and the most
widely prescribed drug for chronic plaque psoriasis.
DMF is thought to be the active ingredient in Fumaderm® and is regarded
as a pro-drug as it is rapidly bound to glutathione (GSH) before absorption
to form a stable adduct. It also undergoes hydrolysis to monomethylfumarate
(MMF). Both the DMF–GSH adduct and MMF can be detected in the blood after
oral DMF administration.
FAEs have immunomodulatory actions without being immunosuppressants.
Their therapeutic effects may relate to protecting cells against oxidative
stress. Binding of DMF to GSH seems to be a crucial step and causes a shift
in cellular redox balance. This leads to activation and stabilization of nuclear
factor (erythroid-derived 2)-like 2 (Nrf2), which induces the production of
many cytoprotective proteins. These include the enzymes NADPH-quinoneoxidoreductase-1 and heme-oxygenase-1 which catalyse the reduction
and detoxification of highly reactive quinones and heme respectively, and
glutathione transferase. Incubation of cells with DMF leads to an initial GSHdepletion (due to its binding), which is followed by a subsequent rise in
intracellular GSH levels. Effects of MMF appear to be related to binding to
the membrane receptor hydroxycarboxylic acid receptor 2 and modulation of
downstream pathways.
The immunomodulatory effects of Fumaderm® in psoriasis may relate to a
shift towards type II dendritic cells releasing interleukin (IL)-10 instead of IL-12
and IL-23, and a subsequent induction of IL-4 producing Th2 cells.
++Indications & dermatological uses
In 2013, the USA FDA and EMA licensed a formulation containing DMF for the
treatment of adults with relapsing remitting multiple sclerosis. This differs from
Fumaderm, which contains a mixture of DMF and ethyl hydrogenfumarate.
Fumaderm® was authorized for the treatment of moderate to severe
psoriasis in adults in Germany in 1994, but is not licensed elsewhere in the
European Union or USA.
FAE therapy has been reported to benefit other dermatological diseases,
including disseminated granuloma anulare, necrobiosis lipoidica and sarcoidosis.
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++Formulations/Presentation
Branded formulation with tablet size of 30 mg (Fumaderm® initial) and 120 mg
(Fumaderm®) containing DMF and three salts of ethyl hydrogenfumarate.
++Dosages & suggested regimens
Therapy with FAE should be initiated with one tablet of Fumaderm® initial
daily and a weekly dose increase to a maximum of three tablets per day to
improve gastrointestinal (GI) tolerance. After 3 weeks, treatment is continued
with Fumaderm® tablets with a similar dose escalation until a satisfactory
clinical response is achieved. The maximum dose is two tablets tds (see Table
1). There is evidence from a retrospective study that many patients respond
well to three or four tablets a day and that further dose increases bring little
clinical benefit. If patients suffer from GI side-effects or flushing, it may be
advisable to reduce the frequency of dosing and use a twice rather than three
times a day regimen, e.g. 1–0–2 instead of 1–1–1 tablets per day. As a general
guide, if side-effects occur dosage should be reduced to the last tolerated dose.
A further dose increase can be reattempted if necessary and may be better
tolerated after a longer treatment period.
TABLE 1 Dosage regimen for Fumaderm® therapy in psoriasis
Fumaderm® initial
Week 1
1–0–0
Week 2
1–0–1
Week 3
1–1–1
Fumaderm®
Week 4
1–0–0
Week 5
1–0–1
Week 6
1–1–1
Week 7
2–1–1
Week 8
2–1–2
Week 9
2–2–2
During maintenance therapy the dosage is gradually reduced to the lowest
dose that is necessary to maintain efficacy; two to four tablets per day in most
patients. In a small minority very low doses (<120 mg daily) may be effective.
Therapeutic dosage is not related to bodyweight or disease activity and is not
predictable in advance.
A clinical response is expected within 6 weeks, although the onset of
action is highly variable due to the personal dosing regimen. Full therapeutic
effects may take several months. Treatment should be discontinued if there is
insufficient improvement by 24 weeks. Prolonged maintenance therapy may
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be considered for disease control. A meta-analysis of randomized controlled
trials for moderate-to-severe psoriasis reported that FAE therapy had similar
efficacy to methotrexate.
As no relapse or rebound phenomena occur after cessation of treatment
with FAE, therapy can be discontinued abruptly if necessary due to adverse
effects or lack of efficacy.
++Baseline investigations & considerations
•
•
•
•
FBC (CBC) with differential WBC.
Urea, electrolytes and creatinine.
LFTs.
Urinalysis.
++Monitoring
During the first 3 months of therapy the following should be checked every 2
weeks, thereafter monthly:
• FBC.
• Urea, electrolytes and creatinine.
• LFTs.
• Urinalysis.
The differential FBC should be checked to identify any downward trend in
the lymphocyte count, which is a common adverse effect of FAE therapy. If
leukocytes decrease below 3000/µL or lymphocytes below 500/µL, treatment
should be stopped. If the lymphocyte count decreases below 0.7 × 109/L the
dosage should be halved and FBC retested after 2–4 weeks. If there is no
recovery a further dose reduction is necessary.
Eosinophilia is a common finding and usually appears after 4–10 weeks of
treatment. It is usually transient without clinical implications. If a persistent
eosinophilia of 25% or more occurs treatment should be stopped. Less
commonly observed side-effects include elevated serum creatinine (>30%
increase above baseline value). Dosage should be reduced and treatment
discontinued if these abnormalities persist.
Proteinuria is usually transient and reversible after dose reduction and
normally without clinical relevance.
++Contraindications
FAE are contraindicated in the following situations:
• Chronic GI diseases including chronic gastritis and active or recent peptic
ulceration.
• Severe liver or kidney diseases.
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• Pregnancy.
• Lactation.
• Chronic diseases associated with reduced levels or function of leukocytes.
Special point
DMF has recently been identified as a potent contact allergen which has been
used as a mould retarding agent for leather items of clothing and furniture.
It is unknown if this is of clinical relevance when considering oral therapy;
however, there is a theoretical risk of eliciting a widespread dermatitis in
patients with known contact hypersensitivity to DMF.
++Cautions
• Renal impairment/proteinuria.
• Lymphopenia.
FAEs do not appear to have an immunosuppressive effect and there is no apparent increase in the rate of common infections associated with their use.
There have however, been recent isolated reports of progressive multifocal
leukoencephalopathy associated with long-term use in patients with lymphopenia below the threshold of 500 µL (see Adverse effects & their management.
++Important drug interactions
FAE have no known important interactions with other drugs. Experience
of combination therapy with FAE and methotrexate, psoralen, retinoids,
ciclosporin (cyclosporine) or other systemic psoriasis therapy remains very
limited and is not recommended, but may be considered in exceptional cases
with close monitoring. Concomitant use of potentially nephrotoxic agents
should be avoided.
++Adverse effects & their management
• Gastrointestinal: complaints such as diarrhoea, abdominal pain, stomach
cramps and nausea are very common adverse effects of FAE and are
dose dependent. They affect up to two-thirds of patients and if severe may
lead to discontinuation of treatment. These symptoms are most troublesome
in the first 3 months of treatment and tend to improve with time. Taking
medication with milk or other dairy products, or mebeverine hydrochloride
taken 30 minutes prior to ingestion may improve GI tolerance.
• Flushing: 30–50% of patients experience flushing after taking FAEs. This
can vary from mild redness and increased warmth for a few minutes to
severe and long-lasting facial redness with associated headaches. Drug
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•
•
•
•
•
withdrawal may be necessary in severe cases. Recently it was shown that
the main metabolite of DMF, MMF, a potent agonist of the hydroxycarboxylic acid receptor 2 expressed on epidermal Langerhans cells and
keratinocytes, induces synthesis of vasoactive prostaglandins D2 and E2 that
cause flushing. Cyclo-oxygenase inhibitors such as aspirin may be helpful in
reducing symptoms.
Haematological:
abnormal
haematological
parameters
especially
lymphopenia and eosinophilia are common and reversible on dose reduction
or withdrawal (see Monitoring for specific advice).
Hepatotoxicity: changes in LFT are rare and normalize rapidly after dose
reduction or cessation of treatment in most patients. Rarely, an isolated
increase in ALT levels or bilirubin has been observed at the beginning of
treatment. Dose reduction or discontinuation of treatment should be
considered if transaminases or GGT rise over twofold the upper limit of
normal, and no other cause for the increase is found.
Malignancy: no increased overall risk of malignancy has been reported
in short- or long-term use of FAE. There are conflicting data regarding a
possible occurrence of melanoma as two case reports describe the detection
of melanoma in patients treated with Fumaderm® for psoriasis. On the
other hand, experimental data in a mouse model of melanoma growth and
metastasis, DMF show inhibitory effects and prolong overall survival.
Nephrotoxicity: renal side-effects are rare and usually resolve after dose
reduction or cessation of treatment (see Monitoring). There have been
rare isolated reports of Fanconi syndrome secondary to FAE therapy. This
is characterized by glycosuria, proteinuria and hyperphosphaturia, and
is caused by proximal tubular dysfunction. It is fully reversible with drug
discontinuation.
Progressive multifocal leukoencephalopathy (PML) has been reported
in two patients treated with FAE. This condition develops when latent JC
virus infection becomes reactivated in patients with immunosuppression.
Prolonged lymphopenia may have been a relevant risk factor in these cases.
++Use in special situations
Pregnancy (FDA Category C)/Lactation
Animal studies of DMF have shown evidence of embryo-fetal toxicity. There
are no established human studies on FAE in pregnancy and the manufacturers
advise that Fumaderm® is contraindicated in pregnancy and lactation.
Children
FAE are not licensed for use in children and adolescents and experience in this
age group is very limited. However, they have been reported in single cases and
small case series to be effective and safe and may be an attractive therapeutic
alternative to systemic immunosuppressants.Careful counselling and detailed
information should be provided to the parents and their informed consent
obtained.
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Elderly
FAE can be used in the elderly in the absence of the contraindications listed
above. The lack of known drug interactions and lack of immunosuppressive
effects is a particular advantage in this age group who often suffer from comorbidities and the need for co-medication.
++Essential patient information
Detailed patient information is important to improve adherence and reduce
treatment drop out due to adverse effects. Dose regimens can be tailored to
individual patients if adverse effects are not tolerated.
The onset of action is relatively slow and additional topical psoriasis therapy
should be continued at the beginning of treatment. Patients should clearly
understand the need to comply with regular blood testing to minimize the risk
of adverse effects.
With acknowledgements to Robert Chalmers, author of this chapter in the
1st edition, and Melinda Gooderham, who reviewed this chapter from an
international perspective.
++Further reading
Balak DM, Oostveen AM, Bousema MT, et al. Effectiveness and safety of fumaric
acid esters in children with psoriasis: a retrospective analysis of 14 patients from
the Netherlands. Br J Dermatol 2013;168:1343–7.
Meissner M, Valesky EM, Kippenberger S, Kaufmann R. Dimethyl fumarate –
only an anti-psoriatic medication? J Dtsch Dermatol Ges 2012;10:793–801.
Mrowietz U, Altmeyer P, Bieber T, et al. Treatment of psoriasis with fumaric acid
esters (Fumaderm). J Dtsch Dermatol Ges 2007;5(8):716–17.
Nast A, Boehncke WH, Mrowietz U, et al. S3 – Guidelines on the treatment
of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012;10
(Suppl. 2):S1–95.
Reich K, Thaci D, Mrowietz U, et al. Efficacy and safety of fumaric acid esters in
the long-term treatment of psoriasis – a retrospective study (FUTURE). J Dtsch
Dermatol Ges 2009;7:603–11.
Rostami Yazdi M, Mrowietz U. Fumaric acid esters. Clin Dermatol 2008;26:522–6.
Schmitt J, Rosumeck S, Thomsachewski G, Sporbeck B, Haufe E, Nast A. Efficacy
and safety of systemic treatments for moderate-to severe psoriasis: metaanalysis of randomized controlled trials. Br J Dermatol 2014;170:274–303.
Walker F, Adamczyk A, Kellerer C, et al. Fumaderm in daily practice for psoriasis:
dosing, efficacy and quality of life. Br J Dermatol 2014;171:1197–205.
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Hydroxycarbamide
Ekaterina Burova
++Classification & mode of action
Hydroxycarbamide (hydroxyurea) was first synthesized in 1869 and then
forgotten until 100 years later, when it was used to treat solid tumours. It was
approved by the FDA in 1967 for the treatment of chronic myeloid leukaemia.
Subsequently, the drug was reported to be effective in the management of
psoriasis and of benefit in patients who had failed to respond to methotrexate
or had underlying liver disease.
Hydroxycarbamide is an S-phase specific antimetabolite that inhibits
DNA synthesis (but not RNA synthesis) through its action on ribonucleotide
diphosphate reductase. This enzyme catalyses formation of deoxyribonucleotides
from ribonucleotides, which in turn are used in the synthesis of DNA. Repair of
DNA damaged by chemicals or irradiation is also inhibited. It is postulated that
hydroxycarbamide’s effects in psoriasis are due to a reduction in keratinocyte
proliferation in the basal layer of the epidermis or on proliferating lymphoid
cells. It also has antiretroviral effects in human immunodeficiency virus (HIV)
infection, inhibiting viral DNA synthesis, and acts in synergy with nucleoside
reverse transcriptase inhibitors (NRTIs). Some effects of hydroxycarbamide may
be mediated by nitric oxide.
Hydroxycarbamide has a low molecular weight (76 Da) (Figure 1). It is
nearly completely absorbed within 2 hours following oral ingestion and widely
distributed in the body. It is metabolized in the liver then mainly eliminated by
the kidneys, with 80% of an oral or i/v dose recovered in urine within 12 hours. It
crosses the blood–brain barrier. There are wide differences in pharmacokinetics
in individuals that may influence its effectiveness.
NHOH
FIGURE 1 Structure of hydroxycarbamide.
O
C
NH2
++Indications & dermatological uses
The licensed indications of hydroxycarbamide in the UK and USA are:
• Chronic myeloid leukaemia.
• Cancer of the cervix (in conjunction with radiotherapy).
• Sickle cell disease: to reduce the frequency of crises and requirements for
transfusion.
It is also used in polycythaemia vera, essential thrombocythaemia and other
malignant diseases. All dermatological use of hydroxycarbamide is off label.
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It may be considered as a systemic therapy for severe psoriasis in patients
who have failed to respond to licensed drugs such as methotrexate, acitretin
or ciclosporin (cyclosporine) and is also a second-line drug in patients with
underlying HIV infection. In general, it is less effective than conventional
systemic therapy. Hydroxycarbamide is more effective in the treatment of
plaque psoriasis than pustular psoriasis or guttate psoriasis and does not
appear to be effective in palmoplantar pustulosis.
++Formulations/Presentation
• Hard capsules containing 500 mg hydroxycarbamide.
• Film coated scored tablets containing 100 mg and 1000 mg hydroxycarbamide.
Capsules and tablets should be taken with water or a small quantity of food
to disguise the bitter taste. In those who are unable to swallow, capsules may
be opened into water and drunk immediately. If the prescribed dose requires
breaking the tablet, this should be performed away from food and any
spilled powder carefully discarded. Patients should be warned not to allow
the powder to come into contact with skin and mucous membranes. Anyone
handling the drug should wear disposable gloves. Hydroxycarbamide should
be stored safely, away from children and pets.
++Dosages & suggested regimens
The usual adult starting dose in psoriasis is 500 mg–1 g daily in one or two
divided doses. A typical maintenance dose is 1–1.5 g daily with a maximum
recommended dose of 2 g daily (20–30 mg/kg). It has been used at doses of up
to 3 g a day, subject to tolerance.
The onset of action is slow with clinical response taking up to 12 weeks.
Reported response rates have varied widely and there is a lack of clinical trial
data to support its use. Nevertheless, it may be of benefit in individual cases,
especially as maintenance therapy after control of psoriasis is obtained with
other systemic medication. Treatment should be discontinued after 12 weeks if
the response is inadequate.
Most dermatological experience with hydroxycarbamide is as a monotherapy
but there have been isolated reports of its use with other systemic treatment,
including biologics. A lower daily dose of 600 mg hydroxycarbamide has been
advocated for use in HIV in combination with other antiretroviral therapy.
++Baseline investigations & considerations
•
•
•
•
FBC (CBC) and differential white blood cell count (WBC).
Urea, electrolytes and creatinine.
LFTs.
Serum urate.
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•
•
•
•
Urinalysis.
HIV hepatitis B & hepatitis C virus infection.
B12 and folate.
Baseline examination of skin for malignancy and ensure cervical screening
is up-to-date.
• Consider testing varicella antibody status if a history of chickenpox is
uncertain. Varicella zoster vaccination should also be given to the nonimmune prior to treatment. Those eligible should receive their ‘shingles
vaccination’ prior to starting therapy. (In the USA this is recommended for
those over 60 years and in the UK, those aged 70–79 years.)
• Influenza and pneumococcal vaccination are recommended prior to starting
hydroxycarbamide, followed by annual influenza vaccination.
• Radiotherapy: an exacerbation of erythema caused by previous or
simultaneous irradiation may occur.
++Monitoring
• Bone marrow toxicity may occur at any stage during the treatment. Therapy
with hydroxycarbamide requires close supervision.
• FBC and differential WBC should be checked once every 1–2 weeks for at
least the first 6 weeks. Intervals between tests can gradually increase every
4 weeks to a maximum interval of 2–3 months long term.
• B12 and folate should be checked in patients with mean corpuscular volume
(MCV) >105 fL to exclude co-existent deficiencies, which can be masked by
drug induced macrocytosis.
• LFTs, urea, electrolytes and creatinine should be monitored at regular
intervals. Once stable this can be reduced to every 3–6 months. A full skin
examination for malignancy should be conducted every 6 months (see
below).
++Contraindications
• Bone marrow suppression. Hydroxycarbamide often causes bone marrow
suppression (see below) and is therefore contraindicated in patients with
leukopenia: WBC <2.5 × 109/L; thrombocytopenia: <100 × 109/L; or severe
anaemia.
• Hypersensitivity to hydroxycarbamide.
• Severe renal and liver impairment.
• Pregnancy and lactation (see below).
++Cautions
• Unstable and fulminant psoriasis.
• Mild to moderate renal impairment.
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• Hyperuricaemia.
• Hepatic impairment.
• HIV infection: hydroxycarbamide may affect the efficacy and toxicity of
antiretroviral medication so close collaboration with HIV physicians is
advised.
• Severe photodamage, actinic dysplasia or history of cutaneous squamous
cell carcinoma.
++Important drug interactions
• Antiretroviral drugs. If used in combination with NRTIs didanosine and
stavudine, their toxicity is enhanced (risk of including pancreatitis, hepatitis
and peripheral neuropathy) so dose reduction and expert advice from a HIV
physician is required.
• Clozapine (antipsychotic), due to increased risk of agranulocytosis.
• Uricosuric therapy may need to be adjusted as hydroxycarbamide may raise
serum urate levels.
• Digoxin absorption may be reduced.
• Interferon-alpha administration has been associated with vasculopathy
including digital infarcts and gangrene in patients with chronic myeloid
leukaemia who also received hydroxycarbamide.
• Live vaccines should be avoided by patients receiving hydroxycarbamide
and those living in the same household. These include oral polio, mumps,
measles, rubella (MMR), bacillus Calmette–Guérin (BCG) and yellow fever.
++Adverse effects & their management
• Myelosuppression is the major concern Is dose dependent and usually
manifests first with neutropenia, followed by thrombocytopenia and
anaemia. Treatment should be stopped immediately if:
• Haemoglobin decreases by 3 g/L.
• WBC <2.5 × 109/L (dose reduction and increase monitoring if <4 × 109/L).
• Neutrophils <1 × 109/L.
• Platelet count <100 × 109/L.
Haematological recovery usually occurs within 2 weeks. Treatment may then be
restarted at a reduced dose.
• Macrocytosis: a raised median cell volume (MCV) and megaloblastic change
is often seen at the start of the treatment and is usually self-limiting.
Morphological changes are similar to pernicious anaemia, but are not
related to B12 or folic acid deficiency.
• Skin and mucosal toxicities are common adverse effects in patients with
myeloproliferative neoplasms and may be related to cumulative dosage.
Painful leg ulcers, resembling pyoderma gangrenosum are characteristic,
especially in the malleolar area in patients with polycythaemia vera.
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Hydroxycarbamide
•
•
•
•
•
Aphthous ulcers of the oral and genital mucosa may occur and painful
erosive stomatitis and glossitis. The drug should be discontinued if ulcers
develop. Leg ulcers are often difficult to treat and slow to heal. Atrophic
skin changes may be localized to the acral areas or generalized and a
dermatomyositis-like eruption may occur, probably related to drug induced
phototoxicity. Palmoplantar erythema is a frequent finding. Other reported
effects include diffuse hyperpigmentation, sclerodermatous change,
leukocytoclastic vasculitis, melanonychia and alopecia.
Malignancy: actinic keratosis and rare cases of cutaneous squamous
cell carcinomas have been reported so regular skin examination and sun
protection advice is recommended, and are essential in geographic locations
exposed to high levels of ultraviolet (UV) radiation. Treatment related
actinic keratoses and intraepidermal carcinoma resolve within months of
discontinuing hydroxycarbamide. Secondary leukaemia has been reported in
patients on long-term hydroxycarbamide treatment for myeloproliferative
disorders. This may be drug or disease related.
Serum urate levels may be increased resulting in gout or uric acid
nephropathy, especially if used with other cytotoxic agents. It is important
to maintain adequate fluid intake during treatment.
Gastrointestinal toxicity is usually mild and may manifest with anorexia,
nausea, vomiting, constipation, diarrhoea and abdominal pain.
Neurological: hydroxycarbamide may cause headache, dizziness and malaise.
Varicella zoster exposure: may lead to severe infection in the non-immune
who should receive varicella immunoglobulin (VZIG) if exposed to
chickenpox and herpes zoster.
++Use in special situations
Pre-conception
Spermatogenesis: hydroxycarbamide may be genotoxic. Males receiving
treatment are therefore advised to use condoms during and for at least 3
months after therapy. They should be informed about the possibility of sperm
conservation before starting treatment.
Pregnancy (FDA Category D)
Females of childbearing age should avoid becoming pregnant, and use effective
contraception. Hydroxycarbamide crosses the placenta and animal studies
have shown it to be a teratogen, producing a range of skeletal malformations,
though the risk in humans is unclear. Patients on hydroxycarbamide wishing
to conceive should stop treatment 3–6 months before pregnancy if possible.
In case of exposure to hydroxycarbamide during pregnancy in female patients
or pregnant partners of male patients treated by hydroxycarbamide, a careful
obstetric follow-up with ultrasound examination should be considered.
Hydroxycarbamide can pass into body fluids (urine, faeces, semen, vaginal
fluid) and these should not be handled by pregnant women.
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Lactation
Hydroxycarbamide is excreted in human milk. Because of the potential for
serious adverse reactions in infants, breastfeeding must be discontinued.
Children
Hydroxycarbamide has been used widely in children over the age of 2 years
with sickle cell disease and is usually tolerated at doses up to 25–30 mg/kg/day.
Elderly
The elderly may be more susceptible to the adverse effects of hydroxycarbamide
due to reduced renal function, so a reduced dose is recommended.
++Essential patient information
Patients should be advised to seek urgent medical advice if they experience
unexplained bleeding, bruising, sore throat, oral ulceration or fever.
With acknowledgements to Annmarie Powell and John Coterill, authors of this
chapter in the 1st edition, and Amanda Oakley who reviewed this chapter from
an international perspective.
++Further reading
Griffiths CEM, Clark CM, Chalmers CM, LiWanPo A, Williams HC. A systematic
review of treatments for severe psoriasis. Health Technol Assess 2000;4(40)
1–125.
Lebwohl M, Menter A, Koo J, Feldman SR. Combination therapy to treat
moderate to severe psoriasis. J Am Acad Dermatol 2004;50(3):416–30.
Lisziewicz J, Foli A, Wainberg M, Lori F. Hydroxyurea in the treatment of HIV
infection: Clinical efficacy and safety concerns. Drug Safety 2003;26(9):605–24.
Lori R, Pollare RB, Whitman L, et al. Lowering the dose of hydroxyurea
minimizes toxicity and maximizes anti-HIV potency. AIDS Res Hum Retroviruses
2005;21:263–72.
Menon K, Van Voorhees AS, Bebo BF, et al. Psoriasis in patients with HIV
infection. J Am Acad Dermatol 2010;62(2):291–9.
Sanchez-Palacios C, Guitos J. Hydroxyurea-associated squamous dysplasia. J Am
Acad Dermatol 2004;51(2):293–300.
Smith CH. Use of hydroxuyrea in psoriasis. Clin Exp Dermatol 1999;24:2–6.
Vassallo C, Passamonti F, Merante S, et al. Muco-cutaneous changes during
long-term therapy with hydroxyurea in chronic myeloid leukaemia. Clin Exp
Dermatol 2001;26:141–8.
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Interferons
Louise A. Fearfield
++Classification & mode of action
Interferons (IFNs) are glycoprotein cytokines, first discovered in the 1950s by
Isaacs and Lindeman. They have immunomodulatory, antiproliferative and
anti-infective actions and are released by host cells in response to pathogens or
tumour cells. They are especially important in protection against viral infection.
Three classes of IFNs are recognized (Types I–III IFN) and these differ in their
protein sequence, receptors, genetic loci and cell types responsible for their
production.
Type I IFNs have an alpha (a)-helical structure and include IFNs-a2 and -beta (b).
There are many subtypes of IFN-a, but only one form of IFN-b. Type II IFN in
humans is IFN-gamma (IFN-g) and Type III IFNs (IFN-lambda, IFN-i) have only
recently been described.
IFN-a is produced by B-lymphocytes and macrophages, and is induced
by foreign cells, virus infected cells, bacteria and tumour cells. IFN-b is
primarily produced by fibroblasts but also by epithelial, endothelial cells and
macrophages, and is induced by viral and other foreign particles. IFN-g is
produced by natural killer cells and T lymphocytes, and is induced by foreign
antigens via specific receptors. IFN-i appears to play an important role in the
protection of epithelial surfaces.
Binding of microbial antigens to receptors such as membrane bound Tolllike receptors or cytoplasmic receptors can trigger release of IFNs, which bind
to specific receptors on the same or neighbouring cells to activate signal
transducer and activator of transcription (STAT) complexes. These regulate the
expression of hundreds of interferon-stimulated genes with antiviral function.
Some STATs are activated by both Type I and Type II IFNs, but each IFN type can
also activate unique STATs.
The antiproliferative effects of IFNs include a direct effect on tumour cells
with prolongation of the cell cycle, inhibition of the expansion of T-cell clones
and activation of cytotoxic T cells. Other actions include increasing p53 activity
and upregulation of major histocompatibility complex molecules MHC I and
MHC II.
IFNs have been used to treat a range of diseases, but their licensed
indications are limited. The addition of polyethylene glycol (PEG) to the
interferon through a process of pegylation, prolongs the half-life of the IFN
compared with its native form.
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IFN-a
++Indications & dermatological uses
Various formulations of IFN-a are commercially available and differ in their
individual product licenses. Indications include the treatment of chronic viral
hepatitis, various haematological malignancies, renal cancer and carcinoid. The
licensed dermatological indications in the UK are as follows below.
Adjuvant therapy of malignant melanoma
The cure rate following surgical removal of early melanoma is high, but patients
with more advanced disease (stage IIB/IIC/III disease [Table 1 overleaf]) are at
higher risk of recurrence and should be considered for adjuvant therapy.
Adjuvant IFN-a has been used for over 10 years at various regimens (low,
medium and high dose >10 MU/dose). High dose IFN-a2b (HDI) has been shown
to prolong disease-free survival, but its effects on overall survival are unclear
and treatment is associated with significant toxicity. IFN-a is licensed as an
adjuvant therapy in patients who are disease-free after surgery but are at high
risk of systemic recurrence. European consensus guidelines from 2012 concluded
that IFN-a may be offered to patients with stage II and stage III melanoma as
an adjuvant therapy as it increases disease-free survival. However, the 2010
British Association of Dermatology melanoma guidelines do not recommend its
routine use for primary or stage III melanoma, due to the lack of clear evidence
for overall survival benefit.
The antitumour actions of IFNs in melanoma are not fully understood, and
may be immunomodulatory rather than cytototoxic. Effects of HDI in melanoma
include recruitment of T lymphocytes and dendritic cells into the tumour and
downregulation of the MEK/ERK MAPK pathway that plays a role in tumour
cell metastasis. Over the last 5 years significant advances have been made in
the treatment of melanoma with novel targeted therapies. These therapies
include BRAF and MEK inhibitors as well as immunomudulatory therapies such
as Ipilumumab and anti-PD1 agents. Currently they are used mainly in stage IV
disease, but have recently been used as adjuvant therapy of stage IIC and above.
There are some current trials investigating combination adjuvant therapy with
HDI and the targeted therapies including Ipilumumab and the BRAF inhibitors.
Addition of HDI to conventional chemotherapy with agents such as cisplatin
and dacarbazine does not appear to confer any benefit in stage IV disease.
Refractory cutaneous T-cell lymphoma
In refractory early stage mycosis fungoides (MF), transformed MF and
folliculotropic MF, a combination of skin directed therapy such as psoralen UVA
(PUVA) plus low dose immodulators (e.g. IFN or bexarotene) may be effective.
Studies of IFN-a2b have shown overall response rates of 45–74% with complete
responses of 10–27%. Various dose schedules have been used and it appears
that response rates are higher for larger doses and for early stage disease. IFN
has also been used in combination with acitretin.
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TABLE 1 The 2009 American Joint Committee on Cancer (AJCC) melanoma
staging system
Stage (M)
Primary tumour (pT)
IA
<1 mm, no ulceration,
mitoses < 1 mm2
IB
<1 mm, with ulceration or
mitoses >/= 1 mm2
IIA
1.01–2 mm, with ulceration
2.01–4 mm, no ulceration
IIB
2.01–4 mm, ulceration
>4 mm, no ulceration
IIC
>4 mm, with ulceration
IIIA
Any Breslow thickness, no
ulceration
Micrometastases
1–3 nodes
IIIB
Any Breslow thickness, with
ulceration
Any Breslow thickness, no
ulceration
Any Breslow thickness, no
ulceration
Micrometastases
1–3 nodes
1–3 palpable
metastatic nodes
No nodes, but in-transit or
satellite metastasis(es)
IIIC
Any Breslow thickness, with
ulceration
Any Breslow thickness, with
or without ulceration
Up to three palpable
lymph nodes
Four or more nodes or
matted nodes or in-transit
disease + lymph nodes
No nodes, but in-transit or
satellite metastasis(es)
Any Breslow thickness, with
ulceration
Lymph nodes (N)
Metastases (M)
IV, M1a
Skin,
subcutaneous
or distant nodal
disease
IV, M1b
Lung metastases
IV, M1c
All other sites or
any other sites of
metastases with
raised lactate
dehydrogenase
In the rare circumstances where mitotic count cannot be accurately determined, a Clark
level of invasion of either IV or V can be used to define T1b melanoma. Every patient
with melanoma should be accurately staged using the AJCC system; this may include
performing a sentinel lymph node biopsy when recommended by the Specialist Skin Cancer
Multidisciplinary Team. Staging should be updated following relapse.
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Kaposi’s sarcoma in association with HIV disease
Kaposi’s sarcoma (KS) remains the most commonly diagnosed malignancy
in HIV-infected patients, and is an acquired immunodeficiency syndrome
(AIDS)-defining diagnosis. The incidence of KS has sharply declined since the
widespread use of highly active antiretroviral therapy (HAART). The first-line
approach to management of HIV associated KS is the initiation/consideration of
HAART under the guidance of a HIV physician. HAART may be combined with
systemic and local therapy. Treatment options include IFN-a and chemotherapy.
For local disease, radiotherapy, intralesional chemotherapy or cryotherapy may
be used. Partial responses in classic (non-HIV associated) KS have also been
reported with IFN, but this is a non-licensed indication. IFN-a is licensed for
the treatment of AIDS patients with progressive, asymptomatic KS who have a
CD4 count >250/mm3. AIDS patients with CD4 counts <250/mm3 or those with
a history of opportunistic infections or constitutional symptoms, are unlikely
to respond.
Unlicensed uses of IFN-a include the following:
Non-melanoma skin cancer
Aggressive non-melanoma skin cancers are therapeutically challenging
and may demand radical, disfiguring surgery. Benefit has been reported in
patients with extensive inoperable or recurrent basal cell carcinoma (BCC) or
squamous cell carcinoma (SCC) given peri- and intralesional IFN-a, three times
per week for 3 weeks, with complete tumour elimination in almost half of
those treated and partial clearance/stable disease in most of the remainder.
IFN may be a therapeutic option in the management of inoperable tumours,
but its role in the management of advanced BCC is likely to diminish since the
advent of vismodegib (see Vismodegib), which is licensed for this indication in
the UK.
Condyloma accuminatum
Locally administered IFN-a has been found to increase the rate of clearance
if tolerated and adverse effects are mild, but treatment is limited to patients
with recalcitrant infection in whom other therapy has failed. Systemically
administered IFN-a appears ineffective.
Infantile haemangiomas
Large infantile haemangiomas are a therapeutic challenge and may cause
life-threatening complications. Several studies have reported the effectiveness
of IFN-a (2a and 2b) in treating these vascular lesions. IFN-a inhibits endothelial
cell migration and proliferation and specific vascular growth factors. As this
mode of action is different to corticosteroids, it can be used in lesions that
are unresponsive to steroids, and it does not need to be given during the
proliferation phase in order to be effective. The onset of action is slower
than corticosteroids, and treatment may need to be continued for up to 12
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months. Due to toxicity, IFN-a is only indicated for induction of early regression
in life-threatening corticosteroid-resistant infantile haemangiomas where
propranolol (see Propranolol) has failed or is contraindicated. The most serious
adverse effect in infants is a potentially irreversible spastic diplegia.
Miscellaneous diseases
Clinical improvement has been reported in patients with cutaneous lupus
erythematosus, treated with IFN-a, but disease tends to relapse rapidly on
stopping therapy. Benefit has also been reported in small numbers of patients
with Ofuji’s papuloerythroderma, lichen planus, recurrent genital herpes and
chronic urticaria. IFN-a has been recommended for severe eye involvement in
Behçet’s syndrome and familial Mediterranean fever resistant to colchicine
treatment.
The combination of pegylated IFN-a with ribavirin and rituximab is
emerging as a promising treatment in hepatitis C virus associated mixed
cryoglobulinemia. Limited data also suggest that IFN may induce remissions in
recalcitrant Churg–Strauss syndrome.
IFN-b
IFN-b is approved for treatment of multiple sclerosis. It has also been used to
treat a number of viral infections including herpes simplex virus and human
papilloma virus and malignant melanoma, but is of no greater benefit than
IFN-a and its current use in dermatological diseases is extremely limited, so it is
not discussed further.
IFN-g
The only licensed indication is chronic granulomatous disease where IFN-g has
been shown to decrease the frequency of serious infections. The use of IFN-g in
dermatology is unlicensed and includes the following (see below).
Atopic dermatitis
The immunopathogenesis of atopic dermatitis (atopic eczema) is complex and
incompletely understood. On the basis of the finding that peripheral blood
mononuclear cells of patients with atopic dermatitis produce lower levels
of IFN-g spontaneously and in response to stimuli, a number of investigators
have studied the clinical effects of recombinant IFN-g therapy in severe
atopic dermatitis. Placebo randomized controlled trials have confirmed the
effectiveness of IFN-g in patients with severe atopic dermatitis, but drawbacks
include cost, frequent injections and a high rate of flu-like symptoms so its use
is limited to a small minority of patients who are unresponsive to conventional
therapy. With increased understanding of the importance of IFN-g in defence
against viral infection, IFN-g therapy may prove most suitable for patients with
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severe eczema who suffer from recurrent widespread viral infection such as
eczema herpeticum.
Miscellaneous
Various other diseases have been reported to respond to IFN-g include Behçet’ s
disease, psoriatic arthritis, scleroderma, keloids, leishmaniasis (both cutaneous
and refractory visceral forms) and eosinophilic pustular folliculitis. IFN-g appears
to be less effective than IFN-a in the treatment of malignant melanoma, HIV
associated KS and cutaneous lymphoma.
++Formulations/Presentation
• IFN-a2b is available in 1 mL and 2.5 mL vials containing 10 million units/mL
ready for injection and in pre-filled syringes and injection pen devices.
• IFN-g is available in 0.5 mL vials containing 200 µg/mL.
• All preparations should be stored at 2–8°C.
++Dosages & suggested regimens
There are a few standardized regimens for treatment of dermatological
disease with IFNs though doses have varied between different clinical trials.
Some examples are given in Table 2.
TABLE 2 Dosage regimens for therapy with interferons
IFN-a
Condylomata
accuminatum
Malignant
melanoma
Follicular
lymphoma
HIV related Kaposi’s
sarcoma
Intralesionally 1
million units/lesion
for up to 5 lesions in
a single course
Lesions should be
injected 3 times
weekly on alternate
days for 3 weeks
An additional course
may be administered
at 12–16 wk
20 million IU/m2 i/v
5 days a week for
4 weeks
10 million IU/m2 s/c
3 d/wk (every other
day) for 48 weeks
5 mIU s/c 3 days/
week for 18
months
5 mIU s/c daily if
combined with HAART
IM or s/c 30 million
units/m2 3 times a
week until disease
progression or maximal
response has been
achieved after 16 weeks
of treatment Dose
reduction is frequently
required
IFN-g
Atopic dermatitis (unlicensed in UK)
50 µg/m2 once daily by s/c injection
0.5 or 1.5 million units/m2 3 times a week by
s/c injection
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++Baseline investigations & considerations
•
•
•
•
•
•
•
•
FBC (CBC).
Urea, electrolytes and creatinine.
LFTs.
Glucose.
Lipids.
Thyroid stimulating hormone (TSH).
Urinalysis.
ECG if pre-existing cardiac abnormalities.
++Monitoring
IFN-a (and IFN-b):
• FBC with differential WCC and LFTs weekly during induction phase then
monthly throughout therapy.
• Urea, electrolytes and creatinine and lipids: every 1–3 months.
IFN-g:
• FBC, U&E, urea, electrolytes and creatinine, LFTs and urinalysis: every 1–3
months.
++Contraindications
For detailed advice, the individual product literature should be consulted.
General contraindications to IFN therapy include:
• Hypersensitivity to specific interferons.
• Severe cardiac, renal or hepatic dysfunction.
++Cautions
Use with caution in patients with seizure disorders, depression and the elderly.
++Important drug interactions
• Metronidazole and atorvastatin: increased risk of peripheral neuropathy,
neurotoxic effects.
• Theophylline: associated with decreases in clearance and increases in plasma
concentration and elimination half-life of theophylline.
• Zidovudine (AZT): may result in severe bone marrow toxicity, most often
manifested as granulocytopenia and/or thrombocytopenia.
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++Adverse effects & their management
• Flu-like symptoms such as fatigue, fever myalgia, arthralgia, headache,
sweating and chills affect most patients during the first weeks of treatment
with all IFNs. They are usually manageable with simple analgesics and by
administering IFN injections in the evening. Symptoms may improve with
continued therapy as tolerance develops.
• Psychiatric (all IFNs but predominantly IFN-a): side-effects are common,
especially depression, and more rarely, suicidal ideas and attempted suicide.
Irritability, anxiety, insomnia and other behavioural disturbances have also
been reported and additional adverse effects of IFN-a include mood and
personality change. Development of the IFN-a-induced depressive symptoms
may arise through depletion of central and peripheral 5-hydroxytryptamine
(serotonin, 5-HT) and reduction of tryptophan plasma levels. Psychiatric
advice should be obtained if severe symptoms develop.
• Gastrointestinal (GI) adverse effects are common and include nausea,
anorexia, vomiting and diarrhoea and may result in weight loss. Gingival
bleeding and GI haemorrhage have been reported more rarely. Antiemetic
medication and adequate hydration may improve nausea, especially during
i/v administration. Pancreatitis has been reported rarely.
• Neurological (all IFNs but predominantly IFN-a): headache and dizziness are
very common and other neurological effects include impaired concentration,
lethargy, sleep disturbance, confusion, paraesthesia, resting and action
tremor and involuntary movements. Most of the CNS adverse effects are
mild and reversible within a few days to 3 weeks after dose reduction or
discontinuation of therapy. Seizures may occur in up to 1% of patients and
are reversible on discontinuation of the therapy.
• Dermatological (predominantly IFN-a and IFN-b): injection site reactions
are common and various rashes have been reported including psoriasiform,
eczematous and pemphigus-like eruptions. Seborrhoea, dry skin, pruritus
and alopecia may occur.
• Respiratory (all IFNs): common flu-like adverse effects include cough, throat
irritation and rhinosinusitis. Dyspnoea and pneumonia may occur.
• Cardiovascular (all IFNs): cardiovascular adverse effects may include
hypertension and hypotension, cardiac failure and rarely, myocardial
infarction. Cardiomyopathy has also been reported rarely in patients
treated with IFN-a.
• Hepatic (all IFNs): adverse effects have included transient increases of liver
transaminase or alkaline phosphatase and the development of autoimmune
hepatitis.
• Haematological (all IFNs): myelosuppression may occur, particularly a
reduction in granulocytes, so regular monitoring of the FBC is required
throughout therapy.
• Rhabdomyolisis and multiorgan failure have been reported shortly after
starting high dose IFN.
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• Metabolic adverse effects include hypertriglyceridaemia and hyperglycaemia.
Thyroid function may become abnormal (hypo- or hyperthyroidism).
• Autoimmune abnormalities have been reported including vasculitis, lupus
and vitiligo.
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
IFNs are contraindicated during pregnancy unless absolutely necessary. Fertility
may be impaired by IFN-a, which is known to cause miscarriages in primates.
Contraception is recommended for both males and females during treatment.
Spontaneous abortions have been reported in females taking IFN-b for multiple
sclerosis.
Lactation
IFNs should be avoided as there are insufficient data regarding safety in
lactation.
Children
IFN-a has been used safely in children in doses of up to 10 mlU/m2. IFN-g has
been used in children, but the safety and efficacy in infants under 6 months is
not known.
++Essential patient information
Patients should be advised of the common side-effects of flu-like symptoms
and fatigue. Further information can be obtained from www.macmillan.org.
uk.
With acknowledgements to Katharine Acland, author of this chapter in the 1st
edition.
++Further reading
Aldenhoven M, Barlo NP, Sanders CJ. Therapeutic strategies for epidemic
Kaposi’s sarcoma. Int J STD AIDS 2006;17(9):571–8.
Chang TT, Stevens SR. Atopic dermatitis: the role of recombinant IFN-gamma
therapy. Am J Clin Dermatol 2002;3(3):175–83.
Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma.
European consensus-based interdisciplinary guideline – Update 2012. Eur J
Cancer 2012;48:2375–90.
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Marsden JR, Newton-Bishop JA, Burrows L, et al.; British Association
of Dermatologists Clinical Standards Unit. Revised UK guidelines for
the management of cutaneous melanoma 2010. Br J Dermatol 2010;163(2):238–
56.
Moschos S, Edington H, Land S, et al. Neoadjuvant treatment of regional stage
IIIB melanoma with high-dose IFN alfa-2b induces objective tumor regression
in association with modulation of tumor infiltrating host cellular immune
responses. J Clin Oncol 2006;24(19):3164–71.
Pu YG, Zeng ZM, Yu ZJ, Huang N, Deng QW. IFN for the treatment of genital
warts: a systematic review. BMC Infect Dis 2009;9:156.
Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of
Dermatologists and UK Cutaneous Group Guidelines for the Management of
Primary Cutaneous T-Cell Lymphomas. Br J Dermatol 2003;149:1095–107.
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Intravenous
Immunoglobulin
Francisco Kerdel & Luis Dehesa
++Classification & mode of action
Immunoglobulin (Ig) preparations derived from human blood are important
biological agents. They were first used to treat immune deficiency states in
1952. Intravenous immunoglobulin (IVIg) is purified from the pooled human
plasma of 3,000–10,000 healthy donors. Pooling provides the entire array of
antibodies normally present in healthy immunocompetent individuals. Since
there are large numbers of donors, there is a possibility of diluting rare
antibodies that may be present in low concentration.
The manufacturing process is complex and includes important steps such as
careful donor selection, screening of plasma samples for infectious agents and
the use of modern viral inactivation techniques in order to optimize safety.
Standards are set by various regulatory agencies including the FDA, European
Medicines Agency and the World Health Organization (WHO).
Various modifications have been applied to the original technique of
obtaining purified commercial IVIg by ethanolic fractionation of plasma.
Recently, a completely newly engineered purification process combining
caprylate precipitation, viral inactivation and double anion exchange
chromatography has been developed. This procedure yields a highly purified
product in a shorter time and with minimal protein denaturation.
A single donation of whole blood (500 mL) yields approximately 15 mL
of plasma proteins, of which only 2–3 mL is highly concentrated pure
gammaglobulin. IVIg contains relatively pure concentrate of IgG with a
distribution of IgG subclasses corresponding to that of normal serum. The
product may also contain variable amounts of albumin, IgA, IgM, IgE, sugars,
salts, solvents, detergents and buffers. These may affect the tolerability of IVIg
infusions, especially the sugar, salt and/or IgA content. The powder product
that has a longer shelf life is dissolved in sucrose. The sucrose content affects
the osmotic load of the preparation and can increase the risk of acute renal
failure in predisposed individuals.
The exact mechanism of action of IVIg is unclear and may differ in different
diseases. Proposed actions include functional blockade of Fc receptors,
complement inhibition, enhanced steroid sensitivity, modulation of dendritic
cell properties, autoantibody neutralization and inhibition of autoantibody
production, modulation of cytokine and cytokine antagonist production,
signalling through the inhibitory Fc receptor (Fc gamma RIIB) and inhibition
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of keratinocyte apoptosis due to blockade of the death receptor Fas (CD95)
by anti-Fas antibodies. In treating any disease, more than one mechanism
may operate. It is possible that in diseases that have multiple stages, different
mechanisms may play an important role at different stages.
++Indications & dermatological uses
Human normal immunoglobulin (HNIG) is given i/m as protection against
viral infections (hepatitis A, measles and rubella). HNIG is also used as
replacement therapy for patients with congenital agammaglobulinaemia/
hypogammaglobulinaemia, and for the prophylaxis of infection following
bone marrow transplantation and in children with human immunodeficiency
virus (HIV) infection.
IVIg is used to treat various autoimmune and infectious diseases, e.g.
idiopathic (immune) thrombocytopenic purpura (ITP) and Kawasaki’s
disease. Other indications include chronic inflammatory demyelinating
polyneuropathy (CIDP) and the acute form of the disease, Guillan–Barré
syndrome. In dermatology, high dose IVIg has been used with promising results
for the treatment of multiple conditions (see below). However, none of these
indications have been approved by the FDA.
Dermatomyositis
This is the dermatological condition with the highest level of evidence for
treatment with IVIg. Multiple case reports, case series and double-blind,
placebo-controlled clinical trials have demonstrated the efficacy of high dose
IVIg in patients with dermatomyositis. All severe forms of dermatomyositis and/
or polymyositis represent potential indications for the use of IVIg. However, it is
not effective as monotherapy and should be used as adjuvant therapy (together
with corticosteroids with or without immunosuppressants). IVIg therapy is
usually considered as a second-line therapy when steroids have failed or are
contraindicated. However, in patients with a severe progressive course, severe
myolysis or paralysis, initial treatment with IVIg may be justified. Treatment
should be administered for a 6-month period in order to determine efficacy.
A total dose of 2 g/kg/mo is generally recommended and should be infused
over a period of 2–5 days. Usually, about 3–4 treatment cycles are required at
monthly intervals before achieving a significant improvement.
Autoimmune blistering diseases
Adjuvant therapy with IVIg may be considered for all severe, treatment
resistant forms of autoimmune blistering disease. Especially good results have
been reported for the treatment of pemphigus vulgaris, pemphigus foliaceus,
mucous membrane pemphigoid and epidermolysis bullosa acquisita; IVIg may
warrant consideration in severe bullous pemphigoid, linear IgA disease and
paraneoplastic pemphigus. In all these cases, IVIg therapy should be used as
a second-line agent after an adequate trial of systemic steroids and other
immosuppressive agents such as azathioprine or mycophenolate mofetil. As for
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dermatomyositis (see above), IVIg appears to have greater efficacy as adjunctive
therapy than monotherapy and treatment should therefore be combined with
systemic corticosteroids with or without other immunosuppressive agents. IVIg
should be administered for a period of 3–6 months in order to assess its efficacy.
A total dose of 2 g/kg/mo is generally recommended. It could be infused over
a period of 2–5 days or 2–3 days depending on total dose required and the
general health of the patient. Slow infusion of 4–5 hours or longer reduces the
incidence of infusion related side-effects.
Guidelines for the indications, dosage, frequency of administration and
monitoring of IVIg were established by a large panel of experts on blistering
diseases from the USA, Canada and Europe, in a consensus statement entitled
‘Use of IVIg in autoimmune blistering diseases’.
Toxic epidermal necrolysis
Although the early administration of IVIg in toxic epidermal necrolysis (TEN) was
reported to reverse the progression of skin disease with a favourable outcome
(potentially life-saving) some controversy remains about its effectiveness.
Randomized controlled trials are needed to provide a definitive answer. A
systematic review and meta-analysis in 2012 found no clear benefit in subjects
receiving IVIg versus supportive care alone.
In the treatment of TEN IVIg is usually given as monotherapy and
administered as soon as possible after confirmation of the diagnosis. A total
dose of 3–4 g/kg is generally recommended and should be infused in divided
doses over a period of 3–5 days.
Systemic vasculitis
Initial treatment usually consists of high dose corticosteroids with or
without immunosuppressive agents such as cyclophosphamide. In patients
who fail to respond, IVIg may be included as a therapeutic option. Benefit
has been reported in Wegener’s granulomatosis, Churg–Strauss vasculitis,
polyarteritis nodosa, microscopic polyangitis, IgA associated vasculitis and
catastrophic antiphospholipid syndrome. Only in Kawasaki’s syndrome is the
use of IVIg recommended as first-line treatment. However, the early use of
IVIg in Wegener’s granulomatosis or in haemorrhagic necrotizing vasculitis
of the skin may prevent massive tissue destruction. The recommended dose
for the treatment of Kawasaki’s syndrome in children is 1.6–2 g/kg/cycle (as
bolus infusion or given over 2–5 days) in combination with the recommended
administration of acetylsalicylic acid.
Other dermatoses that have been reported to improve with the use of IVIg
include autoimmune chronic urticaria, severe atopic dermatitis, pyoderma
gangrenosum, systemic lupus erythematosus (SLE) and other collagen vascular
diseases, pretibial myxedema and scleromyxedema. The role of IVIg in the
management of these diseases (with the exception of dermatomyositis) awaits
clarification by double-blind, placebo-controlled trials. Although relatively
safe compared with immunosuppressive agents, the high cost, combined with
the logistical issues involved in its administration has limited the use of IVIg in
dermatological diseases.
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++Formulations/Presentation
Different preparations of IVIg for i/v administration exist depending on the
manufacturer. Lyophilized formulations have to be reconstituted with normal
saline, water for injection, or 5% dextrose in water just before treatment
to achieve concentrations of 3–12%. Liquid preparations are also available,
reducing the time required for reconstitution and limiting the risk of error.
Most liquid preparations are available in concentrations of 5% (0.05 g/mL or
1 g/20 mL) or 10% (0.1 g/mL or 1 g/10 mL).
The sugar, sodium, IgA, osmolarity and pH of IVIg vary according to
manufacturer and may influence the rate of adverse effects. A highly purified
product is now available, marketed under the name Gamunex®.
++Dosages & suggested regimens
The doses and regimens of high dose IVIg have varied in different studies.
A total dosage of 2 g/kg bodyweight at monthly intervals given over 2, 3 or 5
consecutive days is recommended. The recommended total dose for treatment
of TEN is 3–4 g/kg administered on 3–5 consecutive days. The speed of the
infusion is carefully monitored and adjusted to reduce the risk of adverse events.
As the half-life of IVIg after i/v infusion is approximately 2–3 weeks,
infusions are initially administered at monthly intervals. After 6 months, a
gradual increase to 6-week intervals can be considered if there is a satisfactory
response. It is usual to prescribe only one treatment cycle of IVIg for TEN and
Kawasaki’s disease.
++Baseline investigations & considerations
•
•
•
•
•
•
FBC (CBC).
Urea, electrolytes and creatinine.
LFTs.
Hepatitis B and C serology.
Antinuclear antibody, rheumatoid factor +/- cryoglobulins.
Quantitative serum immunoglobulins (IgG, IgM, IgA; if IgA is low or absent,
measure anti-IgA antibodies).
++Monitoring
• During infusion, vital signs (BP, heart rate and temperature) should be
monitored every 15–30 minutes, particularly during the initial infusion and
throughout the first course of therapy.
• Post-infusion, FBC should be measured frequently (daily at first then at least
at monthly intervals) for the rare occurrence of Coombs-positive haemolytic
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anaemia (reticulocyte count, haptoglobin) and neutropenia. Renal function
and LFTs should be checked on day 2 or 3 of treatment.
++Contraindications
• Previous anaphylaxis or severe systemic response to Ig preparations.
• Rapidly progressive renal failure.
• Selective IgA deficiency with antibodies to IgA is cited by most manufacturers
as a contraindication to their product. However, an IgA depleted preparation
of IVIg may be used with caution. Selective IgA deficiency occurs in
approximately 1 in 700 of the population so IgA should be measured before
therapy.
• Recent or imminent live virus vaccination (relative contraindication), as the
immune response may be affected.
++Cautions
• Impaired renal function or concurrent nephrotoxic drug therapy.
• Patients at increased risk of thromboembolism (including obesity, prolonged
immobilization, hyperviscosity, cryoglobulinaemia, impaired cardiac
function).
• History of SLE, rheumatoid arthritis.
• History of migraine as IVIg may trigger a migraine attack.
• Diabetes mellitus.
• Sepsis.
• Elderly: In patients over 65 years of age the recommended dose should not
be exceeded. The infusions should be administered at a very slow rate.
++Important drug interactions
No drug interactions have been reported to the date with IVIg products.
• Nephrotoxic drugs should be used with great caution and in consultation
with the treating physician during IVIg therapy. This is emphasized to
minimize the risk of causing acute renal failure.
• Live virus vaccines, such as measles, mumps and rubella, should not be
given for 12 days before or 3 months after IVIg, as the product may contain
antibodies which can interact with these vaccines.
++Adverse effects & their management
With the current careful selection of plasma donors and advances in the
manufacturing and purification of IVIg products, the rate of adverse events
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associated with IVIg infusion has considerably decreased. Most reactions are
mild and self-limiting or easy to treat. Frequently they occur during the first
cycle and often during the first few hours of the infusion.
• Headache, fever, chills, nausea, vomiting, dizziness, flu-like symptoms,
arthralgia, migraine, hypotension and urticarial rash are some of the most
common side-effects. These can usually be overcome by reducing the rate
of infusion, administering non-steroidal anti-inflammatory drugs (NSAIDs)
acetaminophen, corticosteroids and/or antihistamines before beginning the
infusion.
The incidence of adverse events is reported by the manufacturers to be
in the range of 1–15%, and is usually less than 5%, but may be higher in
hypogammaglobulinaemic patients. The management of specific adverse
events is shown in Table 1.
• Although rare, severe adverse events can also occur, especially in patients
with co-morbidities or risk factors. Therefore, it is important to obtain a
complete medical history and to perform a thorough medical evaluation
before initiation of IVIg therapy. Adverse events include aseptic meningitis,
acute renal failure, deep venous thrombosis and/or pulmonary embolism,
myocardial infarction, stroke and anaphylactic shock.
TABLE 1 Adverse effects of IVIg therapy and their management
Minor adverse events
Management
Headache
Paracetamol (acetaminophen)/codeine
Slow rate of infusion
Fever, chills, nausea, vomiting,
dizziness, flu-like symptoms,
arthralgias, sore throat.
Paracetamol
Slow rate of infusion
Migraine
Bed rest
Consider prophylaxis 2 days prior, during,
and 2 days post-therapy with propranolol, or
whichever drug has worked in the past, for future
infusions
Hypotension/hypertension
Slow rate of infusion
Phlebitis at infusion site
Change infusion site
Transient elevation of serum creatinine
Observe
Transient elevation of liver enzymes
Observe
Transient urticarial eruption
Oral antihistamines
Vesicular hand/foot and generalized
eczema
Topical corticosteroids
(continued )
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TABLE 1 (continued )
Severe adverse events (rare)
Management
Aseptic meningitis
Bed rest
Paracetamol/codeine/stronger analgesia. For
future infusions: pre-medicate with cetirizine,
encourage high oral intake of fluids, infuse at a
slow rate and the most dilute solution available
Check if patient or family has history of migraines
Acute renal failure
Slow rate, low IVIg concentration, sucrose-free
preparations
Supportive haemodialysis
Anaphylactic shock
Intravenous hydrocortisone + antihistamines,
intravenous fluids +/- adrenaline
Deep venous thrombosis (DVT)/
pulmonary embolism (PE)
Stop infusion
Specific treatment of DVT or PE
Consult vascular surgeon to prevent a future
recurrence
Myocardial infarction (MI)
Stop infusion
Specific treatment of MI
In practice, when prescribing IVIg, it is important to consider underlying risk
factors and choose a brand of IVIg with a suitable composition. For example,
in older patients or those with renal dysfunction, use a sugar-free preparation.
Despite the absence of comparative data regarding the incidence of sideeffects among different IVIg brands, the variable content of sugar, sodium,
IgA, pH and osmolarity may influence the occurrence of side-effects. Moreover,
the rate of infusion, concentration and total volume infused are important
contributing factors.
++Use in special situations
Pregnancy (FDA Category C)
There are no animal data regarding the use of IVIg in pregnancy. Manufacturers
recommend that IVIg be administered in pregnancy only if clearly needed.
IVIg has been safely used in pregnant patients with pemphigus vulgaris with
positive outcomes. Benefit has been shown in a number of other conditions in
pregnancy, including antiphospholipid syndrome with recurrent spontaneous
abortions, ITP and pemphigus gestationis. However, IVIg crosses the placenta
and there have been isolated reports of neonatal haemolysis. The potential for
transmission of infectious agents remains a concern.
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Lactation
The proteins in IVIg are likely to be excreted in breast milk without having
an adverse effect on the breastfed infant. However, there is no information
regarding the safety of IVIg during lactation.
Children
High dose IVIg has been used for non-dermatological diseases in children such
as ITP and Kawasaki’s syndrome.
++Essential patient information
Patients should be informed that the product is prepared from human blood
or plasma and the transmission of infectious agents (in particular, currently
unrecognized ones) cannot be excluded.
With acknowledgements to Razzaque Ahmed who reviewed this chapter from
an international perspective.
++Further reading
Ahmed AR, Dahl MV for the Consensus Development Group. Consensus
statement on the use of intravenous immunoglobulin therapy in the
treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol
2003;139:1051–9.
Ahmed AR, Gürcan HM. Use of intravenous immunoglobulin therapy during
pregnancy in patients with pemphigus vulgaris. J Eur Acad Dermatol Venereol
2011;25:1073–9.
Department of Health. Second edition update. Clinical Guidelines for
Immunoglobulin Use. https://www.gov.uk/government/publications/clinicalguidelines-for-immunoglobulin-use-second-edition-update (Accessed April
2015.)
Fernandez AP, Kerdel FA. The use of IVIg therapy in dermatology. Dermatol
Ther 2007;20(4):288–305.
Firoz BF, Henning JS, Zarzabal LA, et al. Toxic epidermal necrolysis: five
years of treatment experience from a burn unit. J Am Acad Dermatol
2012;67:630–5.
Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoblobulin for the
treatment of toxic epidermal necrolysis: a systematic review and meta-analysis.
Brit J Dermatol 2012;167:424–32.
Vecchietti G, Kerl K, Prins C, Kaya G, Saurat JH, French LE. Severe eczematous
skin reaction after high-dose intravenous immunoglobulin infusion. Arch
Dermatol 2006;142:213–17.
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Isotretinoin
Alison Layton
++Classification & mode of action
Oral isotretinoin (13-cis-retinoic acid) is a vitamin A derivative, first approved
by the USA FDA in 1982 for the treatment of severe, recalcitrant acne. Trace
amounts of 13-cis-retinoic acid are detectable in normal human plasma
suggesting that it is an endogenous retinoid.
Oral isotretinoin monotherapy targets all the major pathogenic processes
in acne. It has effects on cell cycle progression, cellular differentiation, cellular
survival and apoptosis, which lead to a decrease in sebum production and
comedogenesis, thereby reducing surface and ductal Propionibacterium acnes
and it has additional anti-inflammatory properties. Isotretinoin is the only
oral retinoid drug which has a profound effect on sebaceous gland activity,
causing sebocyte apoptosis by inducing the expression of neutrophil gelatinase
associated lipocalin. Isotretinoin also impairs metabolism of androgens within
the sebaceous gland, leading to involution and reduced sebum production.
It up-regulates genes encoding differentiation markers, tumour suppressors,
serine proteases and innate immune proteins, with more delayed effects on
extracellular matrix genes and down-regulates numerous genes involve in lipid
metabolism. The drug lacks any direct antimicrobial action against P. acnes
but makes the microenvironment of the pilosebaceous duct less favourable by
inhibition of sebum excretion and reducing the size of the duct. This lowers
bacterial levels, which in turn reduces inflammation. Isotretinoin also modifies
monocyte chemotaxis, which in part explains its anti-inflammatory effects.
Isotretinoin acts as a pro-drug, as it lacks the ability to bind directly to
cellular retinol binding proteins or retinoid nuclear receptors (RAR and RXR)
but it has at least five biologically important metabolites that are agonists for
these receptors: 4-oxo-isotretinoin, tretinoin, 4-oxo-tretinoin, 9-cis-retinoic
acid and 4-oxo-9-cis-retinoic acid.
++Indications & dermatological uses
It is recommended that oral isotretinoin is considered in the following
situations:
• Severe acne including nodulocystic and conglobate variants and extensive
truncal acne.
• Acne with scarring.
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• Persistent acne that has failed to respond to adequate antibiotic therapy,
including late onset acne (typically females in their 20s and 30s).
• Acne associated with psychosocial disability.
Early onset acne, persistent hyperseborrhoea and a strong family history of
acne are relevant factors as these may be associated with more severe or
recalcitrant disease.
Oral isotretinoin has unparalleled efficacy in the treatment of acne with the majority
of sufferers achieving disease clearance. Relapse rates vary according to patient age,
sex, dosage regimens and disease type. It has also been used successfully for the
treatment of severe papulopustular rosacea at low dosage and for severe acneiform
eruptions induced by epidermal growth factor receptor (EGRF) inhibitors. There
are also reports of benefit in hidradenitis suppurativa, cutaneous lupus, pityriasis
rubra pilaris, psoriasis, disorders of keratinization (Darier disease, keratodermas),
photoageing and in the chemoprevention of non-melanoma skin cancer in naevoid
basal cell carcinoma syndrome and xeroderma pigmentosum.
The manufacturers advise that oral isotretinoin should not be used in
pre-pubertal children or children under 12 years; however, it has been used in
this context without harmful effects and may be warranted for severe disease.
++Formulations/Presentation
• Soft capsules containing 5 mg, 10 mg, 20 mg or 40 mg isotretinoin,
depending on the manufacturers.
• Excipients may include soya bean oil (refined, hydrogenated and partially
hydrogenated), gelatine, beeswax and sorbitol (E420). Various colourants
are present in the capsule shell.
++Dosages & suggested regimens
It has been clarified that an isotretinoin dosage of 1 mg/kg/d achieves a better
clearance than 0.5 mg/kg/d over a 4-month period, but leads to increased
mucocutaneous effects that may not be tolerated. The European Directive therefore
recommends a starting dose of 0.5 mg/kg/d, with subsequent dose adjustment
according to clinical response and side-effects. The use of 0.5 mg/kg or lower dosages
at the onset of treatment may reduce the likelihood of an acne flare.
Clinical improvement may not be evident for 6–8 weeks, with continued
improvement over several months and beyond completion of treatment. Early
studies suggest that the cumulative dose is important in preventing relapse in
patients with severe disease and a cumulative dose of 120–150 mg/kg has been
indicated in this context. Severe nodulocystic acne or truncal acne in males may
require more prolonged therapy and daily doses above 1 mg/kg.
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Alternative regimens including intermittent (1 week per month) low
moderate dose (0.25–0.4 mg/kg/d) have been described in the literature. These
may reduce side-effects and the overall cost of therapy but drawbacks include
concerns about increased durations of exposure and therefore teratogenic
risk in fertile females, as well as possible increased frequency of relapse. This
approach is not included in the product license.
If a severe flare occurs, isotretinoin should be stopped or the dose reduced
and oral prednisolone/prednisone (0.5–1 mg/kg/d) given, then tapered over
4–6 weeks. Isolated large nodules can be treated with topical or intralesional
steroids. Macrocomedones should ideally be treated with cautery or hyfrecation
before isotretinoin is considered.
Isotretinoin is fat soluble and should be taken with food (preferably
containing some fat) or a glass of milk to maximize bioavailability. A novel hard
gelatin capsule, lipid rich formulation is available in the USA that has improved
bioavailability when taken without food.
Suggested treatment schedules for unusual forms of acne are listed in
Table 1.
TABLE 1 Suggested treatment schedules for unusual forms of acne
Acne fulminans
Oral prednisolone 0.5–0.1 mg/kg/d for
4–6 weeks
Introduce isotretinoin 0.5 mg/kg/d after
3–4 weeks
Continue isotretinoin for 6–8 months to
reach a cumulative dosage of 120 mg/kg
Pyoderma faciale
Oral prednisolone 0.5–0.1 mg/kg/d for
4–6 weeks
Daily application of a very potent topical
corticosteroid for 1 week
Introduce isotretinoin 0.5 mg/kg/day after
1 week
Continue isotretinoin for 4–6 months
Gram-negative folliculitis
Isotretinoin 0.5–1 mg/kg/d for 4–8 months
Systemic disease
Low starting doses (0.25–0.5 mg/kg/d) and modest increases at 2-monthly
intervals if required for a treatment duration of 24 weeks may be considered
for patients with underlying medical illnesses such as multiple sclerosis,
motor neurone disease or chronic renal failure/dialysis. For those with rare
diseases where there is a paucity of information, one suggested regimen is to
commence isotretinoin at a dose of 20 mg per week and to increase the dose
by 20 mg every subsequent week, so that the patient is taking 20 mg daily by
the 7th week. The cycle can then be repeated with a twice daily dose so that by
the 14th week patients are taking 20 mg twice a day.
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++Baseline investigations & considerations
The Pregnancy Prevention Programme (PPP) for all systemic retinoids includes:
• Pregnancy testing for all females of reproductive age (see below).
• Establishment of effective contraception.
• Counselling regarding teratogenicity for all females.
The following are recommended in all patients:
• FBC (CBC).
• LFTs.
• Fasting lipids.
• Fasting glucose (if family history or known diabetes).
• Document mood/mental health state (see below).
Special point
Oral isotretinoin is a potent teratogen (see Adverse effects and their
management). The European Medicine Control Agency has introduced a PPP
to reduce the risk of pregnancy in females of childbearing age who receive
oral isotretinoin. A more stringent system (iPLEDGE) has been introduced in
the USA.
All females should be carefully counselled about the risk of severe birth
deformity associated with oral isotretinoin and provided with a written
information brochure provided by the manufacturer of the brand being
prescribed.
European guidelines stipulate effective contraception for all sexually active
females and the manufacturers specify use of one or preferably two effective
contraceptive methods including condoms or a cap plus spermicide. Effective
contraception must be started at least 4 weeks before treatment, continued
throughout treatment and for at least 4 weeks following cessation. The ultimate
choice of specific contraceptive method is a decision made between the patient
(and the parent/guardian if relevant) and their consulting physician. Females
who are not sexually active may choose to be exempt from the PPP and should
sign a disclaimer that they are not at risk of pregnancy and fully aware of the
teratogenic risks of treatment (see Appendix 3).
USA recommendations include mandatory simultaneous use of two forms
of contraception at least one of which must be highly effective (tubal ligation,
partner's vasectomy, intrauterine device or combined hormonal birth control
pill/implant/patch).
A negative baseline pregnancy test should ideally be obtained within
2–3 days prior to menstruation and the drug should then be started on the
second or third day of the menstrual cycle. Due to irregular menses, this is not
always possible, but a negative pregnancy test should be documented prior to
starting isotretinoin in this situation. In Europe, no particular form of testing
is specified, while the USA licence stipulates that a negative serum or urine
pregnancy test with a sensitivity of at least 25 MIU/mL must be performed
within the week prior to starting therapy.
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USA monitoring requirements stipulate two negative pregnancy tests
30 days apart before starting therapy. Prescriptions for females who are at risk
of pregnancy are limited to 30 days and are only valid for 7 days. A negative
pregnancy test should be obtained before each repeat prescription and a posttreatment pregnancy test performed 5 weeks after completing therapy to
exclude pregnancy.
++Monitoring
• Pregnancy testing (in females of reproductive age at risk of pregnancy).
• Fasting lipids and LFTs after 1 month; then if normal, at 3 monthly intervals.
• Blood glucose monitoring in patients with diabetes or impaired glucose
tolerance.
++Contraindications
•
•
•
•
Pregnancy (see below).
Lactation.
Uncontrolled severe hyperlipidaemia.
Hypersensitivity to retinoids or excipients.
Patients taking isotretinoin should not donate blood during treatment and for
at least 1 month after stopping therapy.
++Cautions
•
•
•
•
•
•
•
•
Liver disease.
Severe renal impairment (elimination reduced).
Inflammatory bowel disease (IBD) (see Adverse effects & their management).
Diabetes.
Hyperlipidaemia.
Obesity.
Alcohol excess.
Mental health issues (see Adverse effects & their management).
Lower doses or more frequent monitoring may be indicated in these situations.
++Important drug interactions
• Methotrexate may increase the risk of retinoid hepatotoxicity so careful
monitoring is required.
• Carbamazepine levels are reduced by concurrent intake of isotretinoin,
which may lead to loss of seizure control, so carbamazepine levels need
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Isotretinoin
•
•
•
•
close monitoring when both drugs are taken. Isotretinoin does not interact
with phenytoin.
Alcohol: heavy intake of alcohol has been noted to reduce the efficacy of
isotretinoin and may increase the risk of hepatotoxicity.
Tetracyclines should be avoided during isotretinoin therapy as both drugs
can cause pseudotumour cerebri (PTC)/benign intracranial hypertension.
There are reports of combined treatment resulting in PTC and although this
is likely to be idiosyncratic to both drug types, experts advise against their
combined use.
Vitamin A intake should not exceed the recommended dietary allowance
(4,000–5,000 units/d). Supplements are contraindicated due to the risk of
hypervitaminosis/retinoid toxicity.
St John's wort for depression may reduce the effectiveness of hormonal
contraception and should be avoided in females who are reliant on this
form of birth control.
++Adverse effects & their management
• Teratogenicity: it is established that systemic isotretinoin use in early
pregnancy commonly results in fetal abnormalities including craniofacial,
cardiac, thymic and CNS problems. Studies of human exposure to isotretinoin
demonstrate that about 30% of infants will have major malformations. It is
therefore essential that all females are carefully counselled about this risk
and that the PPP is followed with adequate contraception before, during
and after therapy.
• Hyperlipidaemia is common, affecting 30–40% of patients, but drug
induced increases in cholesterol or triglycerides do not usually require
treatment and are dose related, resolving within 4–8 weeks of stopping
therapy. Retinoid induced hyperlipidaemia occurs more frequently in
patients with underlying predisposing factors, e.g. obesity, alcohol excess,
diabetes, familial hyperlipidaemia and concomitant oral contraceptive
use. It may be a predictor of idiopathic hyperlipidaemia in later life. The
increased low-density (LDL) cholesterol and decreased high-density (HDL)
cholesterol in patients receiving retinoids theoretically increases the
possibility of accelerated atherosclerosis and ischaemic heart disease. This
is a consideration in patients undergoing long-term therapy or those with
pre-existing coronary artery disease.
In the first instance, retinoid induced increased levels of triglycerides and
cholesterol can be managed by an appropriate diet and supplementation
with fish oil capsules (omega-3 fatty acids). Lipid lowering drugs may be
indicated in severe hyperlipidaemia. Triglyceride levels >8 mmol/L may be
associated with eruptive xanthomas and acute haemorrhagic pancreatitis.
There have been isolated reports of these events in patients receiving
isotretinoin, but all have occurred in the context of predisposing underlying
medical problems.
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• Psychiatric: mood changes, depression and suicide have been reported as
possible adverse effects of isotretinoin. While acne itself is often associated with
anxiety and depression, there is a possibility that in rare cases depression may
arise as an idiosyncratic reaction to the drug. Patients with a history of bipolar
disorder or family history of psychiatric disorders may be at increased risk.
Pre-existing depression and a history of attempted suicide are not
contraindications to isotretinoin, but it is important to monitor such
patients carefully. The possibility of adverse psychiatric events should be
discussed with patients and if relevant, their family. It is sensible to obtain
the patient's signature to a statement in their records that they understand
and have had the opportunity to discuss and consider these problems.
An enquiry about psychological symptoms should be made at each visit.
The most commonly described symptoms include fatigue, irritability, poor
concentration, tearfulness, apathy and forgetfulness. The following simple
screening questions can be asked:
Over the past 2 weeks have you consistently:
• Felt unusually sad or fed up?
• Lost interest in things that used to interest you or gave you pleasure?
• Felt more short tempered, agitated or irritable than previously?
A number of questionnaires to assess depression are available. The PHQ-9
(see Appendix 1) has been validated in adolescents and provides a quick and
useful tool to assess depression in this vulnerable age group. If significant
depression is identified, then a psychiatric referral is indicated. Increased
aggression has been identified in some male patients and the FDA in the USA
has advised clinicians to warn potential patients about this side-effect. If there
is any doubt, the drug must be stopped.
• Benign intracranial hypertension is a rare complication of retinoid therapy.
Symptoms include a persistent headache that is unresponsive to simple
analgesia, nausea, vomiting and visual disturbance. Patients with these
symptoms should be examined for papilloedema and if present they should
discontinue the drug immediately and be referred for urgent neurological
advice. Mild headache in the absence of other symptoms is common on
starting retinoid therapy.
• Hepatotoxicity: a transient modest rise in liver transaminases is not unusual
but acute hepatitis and jaundice are rare. Abnormalities are most likely
to occur in the context of heavy alcohol intake and alcohol consumption
should be minimized or stopped during isotretinoin therapy. Elevation
of liver enzymes above twice the upper limit of normal should lead to
discontinuation of treatment. If the elevation of liver enzymes is less than
twice the upper limit of normal, the patient can be managed by more
frequent monitoring, e.g. every 2 weeks.
• Mucocutaneous adverse effects especially cheilitis and dryness of the skin
and mucous membranes affect almost all patients receiving isotretinoin
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•
•
•
•
•
•
and are dose related and easily manageable with lip salves and emollients.
An increase in epidermal fragility may occur so patients should avoid wax
epilation. Due to atrophy of the pilosebaceous apparatus, there is delayed
wound healing and it is advised that dermabrasion or laser resurfacing are
deferred until at least 6 months after stopping isotretinoin. Facial erythema
is also common during treatment and increased sensitivity to sunlight may
occur so adequate photo protection is required. Uncommon cutaneous
effects include development of pyogenic granulomas, paronychia and
diffuse alopecia. Severe skin reactions (erythema multiforme, Stevens–
Johnson syndrome and toxic epidermal necrolysis) have been reported in
patients taking isotretinoin but a causal link is not established.
Epistaxis may occur occasionally due to drying of the nasal mucosa.
Petrolatum can relieve dryness and topical antistaphyococcal agents may
also be of benefit.
Impaired hearing has very rarely been reported in association with
isotretinoin.
Ocular adverse effects include conjunctivitis, dry eyes and decreased
tolerance of contact lenses. These may be secondary to meibomian gland
dysfunction and can usually be alleviated by eye drops (‘artificial tears’)
and use of spectacles rather than lenses. A decrease in night vision has
occasionally been reported and may be persistent, which is an important
consideration in those whose employment is dependent on good night
vision. Affected individuals should stop isotretinoin and have their serum
retinol levels checked, with vitamin A supplements given if required. Pilots
should not take isotretinoin and if exposed, can only return to flying
after a satisfactory eye examination. Refractive eye surgery should not be
undertaken within 6 months of treatment with isotretinoin as this can result
in serious sequelae such as corneal ulceration infection and loss of vision.
Myalgia and muscle stiffness occur in a minority of patients, especially those
involved in strenuous exercise. Mildly elevated creatine phosphokinase levels
have been documented in asymptomatic patients but routine monitoring is
not necessary. Patients should be advised to avoid undertaking strenuous
exercise or starting fitness training while taking isotretinoin. For keen
athletes, a treatment course is best started ‘out of season’.
Skeletal changes: children exposed to high doses of isotretinoin are at
risk for premature epiphyseal closure, while adults on long-term therapy
(>2 years) have an increased tendency to develop hyperostosis and
other skeletal changes including calcification of extraspinal tendons and
ligaments, especially ankles, pelvis and knees and diffuse idiopathic skeletal
hyperostosis (DISH)-like changes in the spine. However, the risk of this is
not clearly established. Further investigation with targeted x-rays may be
indicated for persistent atypical musculoskeletal pain.
Gastrointestinal: an association between isotretinoin and inflammatory
bowel disease (IBD) (ulcerative colitis) has been proposed and this has
been the subject of malpractice lawsuits in the USA. However, a recent
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population based French case-control study reported that isotretinoin was
not associated with any increased risk of ulcerative colitis and was associated
with a decreased risk of Crohn's disease. Until clarified, careful counselling
and collaboration with GI physicians is advised for patients with IBD prior
to commencing therapy. Patients should be advised to stop treatment
immediately and seek urgent medical attention if they develop severe GI
symptoms.
++Use in special situations
Pregnancy & pre-conception (FDA Category X)
Isotretinoin is absolutely contraindicated in pregnancy and females should
not become pregnant within at least 1 month of discontinuing treatment (see
Special point above). There is no known effect on fertility. There is no evidence
of impaired fertility or mutagenic risk in males who receive isotretinoin.
Lactation
Isotretinoin is excreted in breast milk and should not be taken by females who
are breastfeeding.
Children
Isotretinoin does not have a licence for use in children under the age of 12
years. However, severe nodular acne in early childhood (infantile acne) may
merit treatment if unresponsive to conventional therapy. In addition, some
patients in the early stages of puberty with marked seborrhoea may fail to
respond to conventional therapy and isotretinoin may be required. The risk of
scarring from these forms of acne is high if not treated promptly.
++Essential patient information
Patients should be warned of the possible side-effects and given an
up-to-date Patient Information Leaflet as provided by the drug manufacturer.
Females should be provided with specific information on teratogenicity
and contraception and the requirements of the PPP. Information should be
provided on the usual frequency of follow-up visits, monitoring requirements
and the contact details of relevant nursing or medical staff should patients or
their family have concerns about serious adverse effects.
With acknowledgements to Gary Peck who reviewed this chapter from an
international perspective.
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++Further reading
Barnes CJ, Eichenfield LF, Lee J, Cunningham BB. A practical approach to the
use of oral isotretinoin for infantile acne. Pediatr Dermatol 2005;22:166–9.
Cunliffe WJ, Stables G. Optimum use of isotretinoin in acne. J Cutan Med Surg
1996;1(Suppl. 2):S2-14–S2-25.
European Dermatology Forum Guidelines on Acne. http://www.euroderm.org/
edf/index.php/edf-guidelines/category/4-guidelines-acne
Goodfiled MJD, Cox NH, Bowser A, et al. Advice on the safe introduction
and continued use of isotretinoin in acne in the UK 2010. Br J Dermatol
2010;162:1172–9.
Layton AM, Dreno BB, Golnick HPM, et al. A review of the European Directive
for prescribing systemic isotretinoin for acne. J Eur Acad Dermatol Venereol
2006;20(7):773–6.
Nast A, Dreno B, Bettoli V, et al. European Evidence-based (S3) guidelines for
the treatment of acne. J Eur Acad Dermatol Venereol 2012;26:1–29.
Racine A, Cuerg A, Bijon A, et al. Isotretinoin and risk of inflammatory bowel
disease: a French nationwide study. Am J Gastroenterol 2014;109:563–9.
Thiboutot D, Golnick H, Bettoli V, et al. New insights into management of acne:
an update from the Global Alliance to Improve Outcomes in Acne Group. J Am
Acad Dermatol 2009;20(7):773–6.
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Ivermectin
Francisco Vega-Lopez & Sara Ritchie
++Classification & mode of action
Ivermectin was developed in the 1970s and is a semi-synthetic derivative of
the avermectins (macrocyclic lactones) that are obtained from fermentation
products of Streptomyces avermectinius. It was initially used in veterinary
practice to treat parasitic diseases in small and large vertebrates, and was first
reported as a treatment for scabies in humans in 1987.
Ivermectin acts against helminths and arthropods by activating glutamategated chloride channels. These receptors are found exclusively in invertebrate
nerve and muscle cells and belong to the pentameric cys-loop receptor family
of ligand-gated ion channels. Ivermectin binding causes ion channel disruption
leading to cell death, and the receptor specificity explains the drug’s high
efficacy and tolerability in humans. High concentrations of ivermectin can cross
the blood–brain barrier and can bind to vertebrate gamma-aminobutyric acid
(GABA) type A and glycine receptors. This can cause GABA-mimetic toxicity with
hypotension, respiratory failure, coma, and even death.
To ensure human safety, the European Medicines Agency has established
an acceptable standard value for fat, liver and kidney tissues from animals;
ivermectin is not licensed for use in animals from which milk or milk derived
products are used for human consumption.
In Africa, more than 25 million people received ivermectin as treatment
for oncocerciasis (river blindness) and lymphatic filariasis (up to 2008). It has
subsequently been given as Mass Drug Administration (administration of drugs
to whole populations irrespective of disease status) once or twice a year. These
parasitic helminth diseases constitute a serious public health burden in tropical
regions, hence the importance of programmes to control and eliminate disease
and interrupt transmission.
++Indications & dermatological uses
Ivermectin is unlicensed in the UK. It can be prescribed when indicated and is
available by ‘special order’ manufacturers and specialist-importing companies.
The indications for ivermectin in the UK are listed below.
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Onchocerciasis and lymphatic filariasis: ivermectin is the drug of choice to
reduce microfilarial load for prolonged periods of 6–12 months. It has been
distributed for more than 25 years in onchocerciasis endemic regions of subSaharan Africa, the Arabian peninsula, and Latin America as part of a public
health initiative. It has been shown that microfilariaI load decreases by 85%
within 48 hours of administration and by up to 95% within a few weeks.
Ivermectin does not kill the adult Onchocerca worms, so treatment needs to
be repeated at 6-monthly intervals for several years to kill the microfilaria
until the natural death of the adult parasites. There have been a few reports
documenting Onchocerca resistance to ivermectin.
Cutaneous larva migrans (creeping eruption) is caused by migration of
animal hookworm larvae in the epidermis and is a self-limiting disease, but if not
treated promptly, skin pathology may persist for months. Ivermectin is the drug
of choice. Repeated treatments with albendazole (see Azole Antihelminths) are
a good alternative if ivermectin is not available.
Strongyloidiasis is caused by a soil transmitted helminth and infected
individuals are often asymptomatic. However, severe, disseminated lifethreatening disease may occur with immunosuppression. Ivermectin is effective
against cutaneous symptoms (larva currens) and systemic disease.
Scabies: severe, crusted or resistant scabies is the main indication for
ivermectin, particularly in the immunocompromised host. It is also first choice
for bed-ridden patients and for institutional out-breaks in prisons, children’s
homes, hospital wards and homes for the elderly. Efficacy and cure rates of
between 85% and 95% have been reported.
Other uses: oral ivermectin has been successfully used to treat orbital and
nasal myasis, scalp pediculosis and Demodex folliculitis. It is safe and effective
against ocular Loa Loa; however, individuals with high parasitic loads are at risk
of developing severe neurological reactions after simultaneous treatment with
ivermectin and diethylcarbamazine (DEC). Ivermectin has been found to decrease
adult survival, fecundity and hatch rate of eggs in Aedes aegypti mosquitoes
and appears to have similar effects in Anopheles, the human malaria vector.
Interest has therefore grown regarding its role as a complementary strategy
in malaria eradication. Benefit has also been reported in treatment of other
soil transmitted helminth infections and gnathostomiasis. An antiviral effect in
human immunodeficiency virus (HIV), and cell death in leukaemia cell lines from
humans and rodents have also been demonstrated.
++Formulations/Presentation
• 3 mg tablets and 6 mg scored tablets.
• Tablets should be swallowed whole with water on an empty stomach.
• In the UK, Oral ivermectin is only available on a named patient basis due to
its unlicensed status.
• A lotion containing 0.5% ivermectin in 0.5% malathion has been found to be
effective in the treatment of head lice in children.
• 1% ivermectin cream is FDA approved fir treatment of papulopustular
rosacea
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++Dosages & suggested regimens
The dose is 200 µg/kg bodyweight given in a single oral dose (see Table 1). The
following regimens are recommended:
• Cutaneous larva migrans: a single dose is usually curative, but if clinical signs
and symptoms persist, treatment can be repeated after 3 weeks.
• Strongyloidiasis: treatment given on 2 consecutive days. This 2-day treatment
is repeated after 2 weeks in the immunosuppressed.
• Onchocerciasis: single dose every 6–12 months is used as treatment and in
Mass Drug Administration (MDA) programmes.
The preferred regimen at the London Hospital for Tropical Diseases is to treat
newly diagnosed patients with imported disease as follows: admit patient
for first dose, then two further doses at monthly intervals as an outpatient,
followed by further doses every 3–6 months.
TABLE 1 Dosage guidelines for ivermectin
Bodyweight (kg)
Single oral dose (number of 3 mg tablets)
15–24
1 tablet
25–35
2 tablets
36–50
3 tablets
51–65
4 tablets
66–79
5 tablets
≥80
calculate as 200 µg/kg
• Severe scabies (see above): single dose repeated after 1 week.
Additional simultaneous treatment with a topical acaricide should be given
on the same days as oral medication. Options include 5% permethrin, 0.5%
malathion or 25% benzyl benzoate (avoid in children). All members of the
same household require simultaneous treatment. Topical keratolytics and oral
antibiotics are indicated for secondarily infected hyperkeratotic lesions.
++Baseline investigations & considerations
Relevant diagnostic investigations should be performed.
• Onchocerciasis is diagnosed on detecting microfilaria in skin snips, positive
serology, eosinophilia and ocular manifestations in those with a history
of exposure in endemic regions of the world. Patients usually have severe
pruritus, which may be accompanied by a papular, lichenified dermatitis.
Other findings include nodules (onchocercomata) on trunk and/or limbs
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and chronic pigmentary changes (patchy hyper- and hypopigmentation)
particularly on the lower limbs. Elimination of Ascaris worms can be observed
as a secondary effect of treatment with ivermectin.
• Cutaneous larva migrans is diagnosed clinically, according to a history of
exposure, intense localized pruritus and a distinctive rash comprising an
erythematous cutaneous larval track often with a positive ‘sign of the loop’.
Eosinophilia and Loeffler’s syndrome have been described and the diagnosis
relies upon a FBC (CBC) with differential white blood cell (WBC) and chest
x-rays.
• Strongyloidiasis can be reliably diagnosed by an enzyme linked
immunosorbent assay (ELISA) serological test and the adult worms can be
detected in stools by several methods, though some of these have limitations
in detecting the larval stages or particular species. Patients may manifest
generalized pruritus, pruritus ani, urticaria and less commonly symptoms of
larva currens.
• Scabies is usually diagnosed clinically and presents with an intensely pruritic
papular eruption with small linear or s-shaped mite tracks (burrows) in
the epidermis, which may be more easily visualized with dermoscopy.
Vesicopustular and nodular lesions may predominate in children. Microscopic
identification of a mite in skin scrapings from a burrow confirms the
diagnosis, but is time consuming and not always practical in a busy clinical
setting.
++Monitoring
• No routine blood monitoring is required.
• Treatment response is usually assessed clinically.
• Patients with onchocerciasis are usually followed up every 3–6 months for
FBC, skin snips and in some cases repeated serology.
++Contraindications
• Pregnancy and lactation.
• Young children.
++Cautions
Severely ill or debilitated individuals and those with neurological disease (due
to potential neurotoxicity at high doses).
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++Important drug interactions
Ivermectin is primarily metabolized by cytochrome 450 (CYP450) 3A4, but does
not inhibit this enzyme and no drug interactions have been identified.
Simultaneous multidrug treatment with ivermectin, praziquantel and
albendazole has been shown to be safe in a study of Ugandan children. When
given with DEC for the treatment of lymphatic filiriasis, systemic reactions may
be potentiated in heavily infected patients due to death of parasites. Common
manifestations include headache, malaise, acute lymphangitis, epididymitis and
abscess formation.
++Adverse effects & their management
Headaches, nausea and vomiting are uncommon. Gastrointestinal symptoms
are usually mild and self-resolving.
Ivermectin is usually well-tolerated by patients receiving treatment for
scabies, cutaneous larva migrans and strongyloidiasis. In cases of onchocerciasis
with heavy microfilaraemia drug reactions can be more severe and similar to
those seen in cases treated with DEC (systemic inflammatory and anaphylactoid
reactions).
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
Ivermectin is contraindicated in pregnancy. Teratogenesis has been widely
described in sheep and cows following use of this drug to treat parasitic and
ectoparasitic diseases.
Lactation
Females taking ivermectin should not breastfeed as the drug is excreted in milk.
Children
It is not recommended for use in children under 5 years of age or weighing less
than 15 kg.
++Essential patient information
The unlicensed nature of this drug should be discussed and females should be
advised to avoid pregnancy while taking treatment.
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++Further reading
Crump A, Morel CM, Omura S. The onchocercciasis chronicle: from the beginning
to the end? Trends Parasitol 2012;28(7):280–8.
Ejere HO, Schwartz, Wormald R, Evans JR. Ivermectin for onchocercal eye disease
(river blindness). Cochrane Database Syst Rev 2012;8:CD002219.
Golant AK, Levitt JO. Scabies: a review of diagnosis and management based on
mite biology. Pediatr Rev 2012;33(1):e1–e12.
Goldust M, Rezaee E, Hemayat S. Treatment of scabies: comparison of permethrin
5% versus ivermectin. J Dermatol 2012;39(6):545–7.
Hoerauf A, Pfarr K, Mand S, Debrah AY, Specht S. Filariasis in Africa – treatment
challenges and prospects. Clin Microbiol Inf 2011;17(7):977–85.
Lynagh T, Lynch JW. Ivermectin binding sites in human and invertebrate
Cys-loop receptors. Trends Pharmacol Sci 2012;33(8):432–41.
Yang CC. Acute human toxicity of macrocyclic lactones. Curr Pharmaceut Biotech
2012;13(6):999–1003.
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Methotrexate
Richard Woolf & Catherine Smith
++Classification & mode of action
Methotrexate (MTX) is a derivative of folic acid and classified as an antimetabolite
cytotoxic agent. It is a pro-drug that is actively transported into cells as
MTX-monoglutamate. Following this further glutamic acid residues are added
to form biologically active methotrexate polyglutamates (Figure 1) that cannot
be transported extracellularly unless hydrolysed back to MTX monoglutamate.
This leads to intracellular accumulation of MTX and therapeutic effectiveness
with once-weekly administration. Free monoglutamated MTX is rapidly cleared
from the serum by renal tubular filtration. In malignant disease, high dose MTX
acts as a folate antagonist, competitively inhibiting dihydrofolate reductase,
thimidylate synthase and other enzymes involved in de novo purine synthesis.
At low doses it has anti-inflammatory actions, which are not diminished by
concomitant administration of folic acid. These are complex and not clearly
understood, but include the release of adenosine that inhibits generation
of reactive oxygen species by polymorphs and proliferation of lymphocytes.
Adenosine may be responsible for some of the adverse effects of MTX including
fatigue and hepatotoxicity.
PG
MTX
Renal
excretion
MTX
MTX
Folate, Purine and
Pyramidine pathways
Adenosine
Anti-proliferative
Anti-inflammatory
FIGURE 1 Methotrexate metabolism in target cell.
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Over the past decade there has been a quest to identify genetic markers
that reliably predict MTX efficacy and toxicity and it is hoped that in the future
these will help to optimize its use.
++Indications & dermatological uses
• Psoriasis. MTX is licensed for the treatment of severe, uncontrolled psoriasis.
It is an effective first-line systemic agent and is considered the gold
standard comparator for new interventions for psoriasis, such as biologics.
It is a well-established treatment for different variants of psoriasis, including
extensive chronic plaque disease, pustular psoriasis, erythrodermic psoriasis
and psoriatic arthritis. Published studies suggest that MTX produces a
reduction in psoriasis severity of at least 50% in approximately two-thirds
of patients. MTX and oral ciclosporin (cyclosporine) have a similar efficacy
in the treatment of psoriasis and the choice of agent is influenced by their
differing side-effect profiles. Benefit has also been reported in a variety of
other inflammatory skin diseases including:
• Atopic dermatitis.
• Lymphoproliferative disorders (lymphomatoid papulosis, mycosis fungoides).
• Bullous pemphigoid.
• Connective tissue disease (recalcitrant cutaneous lupus erythematosus,
dermatomyositis, systemic sclerosis and morphoea) and vasculitides.
• Sarcoidosis.
• Lichen planus.
Methotrexate is also licensed in the treatment of rheumatoid arthritis and
malignancies (at higher doses), such as leukaemia, non-Hodgkin’s lymphoma
and certain solid tumours.
++Formulations/Presentation
• Scored tablets containing 2.5 mg or 10 mg MTX. (NB: Different tablet
strengths may be a source of confusion for patients and increase the risk
of inadvertent overdose; many dermatologists restrict prescribing to 2.5 mg
tablets only to avoid patient error.)
• Parenteral preparations (for i/m, s/c or i/v use): pre-filled syringes containing
between 7.5 mg to 30 mg MTX. Usually these are administered by
clinical staff; however, with appropriate training patients can self-administer
s/c MTX.
++Dosages & suggested regimens
MTX should be given as a once weekly single dose, with or after food, on a
specific day of the week, with explicit verbal and written instructions to the
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patient. A divided dose regimen (i.e. three 12-hourly doses) should be avoided
unless nausea is a significant problem, since the risks of dose error on the part
of the patient are greater. Oral administration is convenient and preferable.
An initial test dose of 5–10 mg (in normal healthy adults) should be given
and FBC (CBC) measured at 1 week. This should detect those that are unduly
sensitive to the drug. If the FBC remains stable, the dose can be increased in
increments of 2.5 mg or 5 mg a week. In the elderly and those with renal
impairment the test dose and the dose increments should be reduced to 2.5 mg
due to the increased risk of MTX accumulation and toxicity. The maintenance
dose should be adjusted according to disease response and kept as low as
possible. Patients whose weekly dose does not exceed 15 mg/wk appear to
have a very low risk of hepatotoxicity. MTX is a slow acting drug and the
complete clinical response for a given dose may take 6–12 weeks to achieve.
The maximum licensed dose in psoriasis is 30 mg/wk. However, disease control
is usually achieved at a lower dose.
If bioavailability or patient compliance is of concern i/m or s/c administration
may be necessary. Although the i/m, s/c and oral routes of administration
are considered equipotent, a modest dose reduction is recommended when
converting from oral to parenteral administration. Also following a treatment
break of several weeks, MTX should be reintroduced at a lower dose (e.g. 5 mg)
and then increased as necessary with appropriate monitoring.
++Baseline investigations & considerations
Baseline liver assessment:
• LFTs including AST and GGT.
• Hepatitis B and C virus.
• Serum PIIINP if available (see Special point).
• Consider liver ultrasound to exclude gross liver pathology.
• Pre-treatment liver biopsy (see Special point): in high risk patients, a liver
biopsy is recommended within the first 4–6 months of therapy. Risks of liver
biopsy may not be considered justifiable in the elderly, in patients with
severe psoriasis where alternative therapies are inappropriate or known
to be ineffective and those who may be particularly vulnerable should
complications occur (e.g. severe ischaemic heart disease).
• Additional investigations may include: in male patients serum ferritin to
exclude haematochromatosis, and in female patients antimitochondrial
autoantibodies to exclude primary biliary cirrhosis.
Special point: Hepatotoxicity
Hepatotoxicity, including liver fibrosis and cirrhosis, is a recognized association
with long-term MTX treatment. MTX hepatotoxicity rarely leads to liver failure
but is an important cause of treatment withdrawal. The pathogenesis of MTX
associated liver fibrosis is not clear and may be multifactorial. Patients on MTX
for rheumatoid arthritis appear to be less at risk of liver toxicity. In patients with
psoriasis, cumulative MTX (exceeding 1.5 g) and type 2 diabetes mellitus, high
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alcohol intake, obesity and viral hepatitis B or C infections are considered risk
factors for hepatotoxicity. However, it is unclear if these co-morbidities, often
seen in patients with psoriasis, are confounders that in themselves predispose
to hepatotoxicity. They should be considered as ‘Cautions’ when initiating MTX
and advice offered on modifiable risk factors before initiating MTX.
Percutaneous liver biopsy is the gold standard for the detection of liver
fibrosis/cirrhosis, but its disadvantages include non-diagnostic results due to
sampling error and even with ultrasound guidance there is a small risk of
serious complications including bleeding and death. Measurement of serial
LFTs is unreliable in detecting chronic MTX hepatotoxicity and there is poor
correlation with histological change. Newer non-invasive diagnostic tests
include measurements of pro-collagen III peptides (type III pro-collagen
aminopeptides; PIIINP) and liver fibroelastography (FibroScan®) which utilizes
ultrasonography to detect liver fibrosis (see Systemic Therapy & Liver Disease).
Serum procollagen III peptide is derived from the synthesis of new type III
collagen and degradation of existing collagen fibrils released into the blood
during active liver fibrosis. This measurement has a sensitivity and specificity
of 74% and 79% respectively, so if normal, it is unlikely that significant liver
fibrosis is present. Factors associated with false-positive PIIINP results are
young age, smoking, non-steroidal anti-inflammatory drugs (NSAIDs) and joint
involvement/arthritis. Serial PIIINP measurement has been adopted by some
UK centres to replace/guide routine liver biopsy. With the emergence of noninvasive diagnostic tests, the risks associated with liver biopsy must be balanced
against the risks of MTX induced liver fibrosis. However, at present, guidelines
for the use of liver biopsy at baseline and during MTX monitoring vary between
countries and specialties. Stratification of patients into those with low or high
risk of MTX hepatotoxicity may be helpful. High risk patients include those
with a history of diabetes, obesity, abnormal LFT results, excessive alcohol
intake and/or chronic liver disease. The PIIINP assay can also be used to identify
high risk patients (a pre-treatment PIIINP of >8.0 mg/L; during treatment at
least three PIIINP results >4.2 mg/L or two consecutive results >8.0 mg/L within
a 12-month period). The American Academy of Dermatology guidelines on the
use of MTX in psoriasis for high risk patients recommend a liver biopsy near
the beginning of therapy, and at each additional 1.0–1.5 g cumulative dose
(provided all other investigations are normal). For low risk patients a baseline
liver biopsy is not routinely recommended, with a biopsy considered after
3.5–4.0 g cumulative dose, and at each additional 1.5 g. In the UK it has been
suggested that pre-treatment liver biopsy is not routinely necessary. If in doubt,
specialist hepatological advice should be sought.
Other baseline investigations:
• FBC, red cell folate.
• Serum electrolytes and renal function.
• Urinalysis (including glucose).
• Glomerular filtration rate (GFR) or creatinine clearance in patients over the
age of 60 years, with a raised serum creatinine level or a history to suggest
potential renal impairment.
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• Chest x-ray: useful in the event of pulmonary symptoms developing and also
to exclude foci of old tuberculosis that may become reactivated as a result
of the immunosuppressive effect of MTX therapy.
• Pregnancy test (urine/serum) in females of childbearing age.
• HIV testing.
• Assessment of disease severity (e.g. Psoriasis Area and Severity Index [PASI],
Body Surface Area [BSA], Physician’s Global Assessment [PGA]) and healthrelated quality of life (e.g. Dermatology Life Quality Index [DLQI], see
Appendix 4).
++Monitoring
• FBC, serum electrolytes, renal function and LFTs:
• Weekly for 2 weeks after each dose increase.
• 8–12 weekly once dose stabilized.
• Red cell folate if MCV increases.
• Serum PIIINP at 3-monthly intervals (if available).
• Liver biopsy: in low risk patients should be considered after 3.5–4.0 g
cumulative dose of MTX, and at each additional 1.5 g. In high risk patients a
liver biopsy is recommended at each additional 1.0–1.5 g cumulative dose of
MTX. This is provided all other investigations are normal (see Special point).
• Assessment of disease severity (as above) to monitor MTX efficacy.
++Contraindications
• Severe haematological abnormality – severe anaemia, leukopenia or
thrombocytopenia.
• Severe liver disease (fibrosis or cirrhosis).
• Severe renal insufficiency (eGFR <20 mL/min).
• Pregnancy or breastfeeding.
• Hypersensitivity to MTX.
• Active peptic ulcer disease.
• Severe and/or active infectious disease.
• Immunodeficiency.
• Significantly reduced lung function.
++Cautions
• Renal impairment, i.e. GFR <50 mL/min: since MTX is renally excreted,
toxic levels may rapidly accumulate in the presence of renal impairment
increasing the risk of myelosuppression. This is particularly liable to occur
in the elderly during episodes of dehydration, or as a result of concomitant
drug administration, e.g. NSAIDs.
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• Pre-existing liver disease or current excessive alcohol intake may predispose
to hepatotoxic effects of MTX.
• Serious infection including HIV infection.
• Gastritis or ulcerative colitis.
• History of malignancy.
++Important drug interactions
• Ciclosporin, leflunamide, azathioprine and sulfasalazine; concomitant use
with nephrotoxic, myelotoxic or hepatotoxic drugs is not recommended.
• NSAIDs, penicillin, colchicine and probenecid may reduce MTX elimination,
leading to increased MTX toxicity. Where NSAIDs are considered essential,
the lower starting dose of 2.5 mg MTX is indicated with monitoring of renal
function after 1 week and at further weekly intervals after dose increases or
changes in NSAID therapy. Ideally, NSAIDs should not be taken on a sporadic
basis, as the effects on MTX levels can be difficult to predict.
• Retinoids may increase the risk of MTX hepatotoxicity.
• Tetracyclines and chloramphenicol displace protein-bound MTX, increasing
serum concentrations that may lead to increased MTX toxicity.
• Trimethoprim, sulphonamides and phenytoin are folate antagonists and
may increase MTX toxicity.
• Radiotherapy: radiation recall (burns) may occur at sites of prior irradiation.
• Live vaccines are contraindicated on theoretical grounds in patients taking
MTX.
• St John’s wort may increase the risk of toxicity.
++Adverse effects & their management
• Folic acid deficiency may arise in patients on MTX and is often identified
by a rise in mean corpuscular volume (MCV). This may be exacerbated by
concomitant medications that have antifolate activity (see Important drug
interactions). If suspected, patients should receive folic acid supplementation
for the duration of MTX therapy. Some physicians recommend routine folic
acid supplementation to reduce the gastrointestinal or hepatic adverse
effects of MTX. Different folic acid dosing regimens have been proposed
including 1–5 mg daily, 1–5 mg daily except for days of MTX and 2.5–5 mg once
weekly 24 hours following MTX dose. There is no convincing evidence that
concomitant folic acid administration reduces MTX efficacy, irrespective of
dosing regimen. It is essential that the regimen for folic acid replacement
is clearly explained to the patient to avoid confusion with MTX and
overdosage of the latter. If the MCV continues to rise (>106 fL) despite folic
acid supplementation and other causes are excluded (B12 deficiency or
alcohol excess), MTX should be discontinued.
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• Gastrointestinal: nausea/vomiting affects about 10% of patients, usually
occurring 12 hours after ingestion and persisting up to 3 days after therapy.
Possible (although unproven) solutions include reducing the dose, adding
folic acid, taking MTX with food, administering MTX i/m, s/c and dividing
the once weekly dose into three doses, given at 12-hourly intervals (see
Dosages and suggested regimens). Malaise, fatigue, dizziness and headache
may occur.
• Myelosuppression may affect up to 20% of patients on long-term therapy
for psoriasis, manifesting as leukopenia, thrombocytopenia, anaemia
or pancytopenia. Myelosuppression is the most common cause of death
due to MTX in psoriasis patients; 22 (85%) of the 26 fatalities associated
with MTX therapy for psoriasis reported to the Committee on Safety of
Medicines (UK) between 1969 and 1995 were related to myelosuppression.
The risk is increased in those with renal impairment, especially in the elderly,
those taking concomitant drugs that reduce MTX excretion, and in folate
deficiency (see above). MTX should be discontinued if severe leukopenia,
thrombocytopenia or anaemia occur.
• Hepatotoxicity: MTX has been associated with both acute and
chronic hepatotoxicity (see Special point). Acute elevation in serum
aminotransferase concentrations frequently occur 1–3 days after a dose
of the drug. These changes are usually transient, asymptomatic and do
not appear to be predictive of subsequent chronic hepatotoxicity. Chronic
hepatotoxicity may manifest as fibrosis or cirrhosis. Studies in patients
with psoriasis treated with MTX have reported widely varying rates of ‘any
stage’ of liver fibrosis (5.7–71.8%), which may relate to sample size and
inconsistency in histopathological classification. In psoriasis the degree of
liver fibrosis appears to be relatively benign with few patients on long-term
MTX progressing to cirrhosis. In addition, the aetiopathogenesis of MTX
associated hepatotoxicity is not fully understood and is likely confounded by
co-morbidities. Withdrawal of MTX in patients who develop MTX induced
cirrhosis may lead to improvement in liver histology and even in those who
continue treatment, progression of cirrhosis leading to liver failure is not
inevitable.
If transaminases (ALT, AST) rise above three times the upper limit of
normal, then MTX should be discontinued. For mild rises in liver tests, a
minor dose reduction may be considered with close monitoring of LFTs to
ensure normalization. Referral to a hepatologist and liver biopsy should be
considered if there is persistent elevation of liver enzymes or PIIINP (at least
three PIIINP results >4.2 mg/L or two consecutive results >8.0 mg/L within a
12-month period).
• Pulmonary toxicity appears to be more common in patients given MTX
for rheumatoid disease and is an idiosyncratic adverse effect. If respiratory
symptoms develop, such as a dry persistent cough, MTX should be stopped
until MTX induced pulmonary toxicity has been excluded.
• Carcinogenicity: the risk of carcinogenicity with MTX appears to be low
when compared with other immunosuppressive agents used for psoriasis,
such as ciclosporin.
• MTX overdose: expert advice should be sought in the event of MTX overdose.
206Clinical manifestations of acute toxicity include myelosuppression, mucosal
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ulceration (particularly oral ulcers) and rarely acute skin ulceration. This latter
complication is occasionally seen in patients with active extensive psoriasis
if the dose of MTX is increased too rapidly. Toxicity can also be precipitated
by factors that interfere with either the renal excretion of the drug, such
as dehydration, or drug interactions. Folinic acid (calcium leucovorin) is a
fully reduced folate coenzyme that can bypass the metabolic effects of MTX.
A source of folinic acid should be identified by the prescribing physician
for use in the event of overdose. It should be given without delay, ideally
within 4 hours of MTX administration, as its efficacy reduces with time. An
initial dose of 20 mg of folinic acid should be given i/v or i/m, followed by
measurement of serum MTX levels if available. Further doses of folinic acid
can be titrated accordingly. If MTX levels cannot be measured, 20 mg of
folinic acid should continue to be given every 6 hours until the blood count
has normalized and mucosae healed.
• MTX osteopathy is a poorly recognized complication of low dose MTX and
is characterized by a triad of severe pain, osteoporosis and compression
fractures, mostly affecting the distal tibia.
++Use in special situations
Pregnancy & pre-conception (FDA Category X)
MTX is strictly contraindicated during pregnancy as it is both an abortifacient
and teratogen. It is advised that MTX therapy should be stopped at 3 months
before conception by both males and females. However, the necessity of this
precaution in males taking low dose MTX has recently been questioned. In the
event of an unplanned pregnancy expert advice should be sought.
Lactation
MTX is contraindicated in lactation as it is excreted in breast milk.
Children
MTX may be used under specialist supervision for children (2–18 years old)
with severe psoriasis requiring second-line therapy, although it is not licensed
for psoriasis in this age group. It is also gaining popularity as a treatment for
severe atopic dermatitis. MTX is given as a once weekly dose, usually initiated
at 0.2 mg/kg, which can be increased to 0.4 mg/kg (max. 25 mg) as guided by
clinical response. The lowest possible dose required to maintain disease control
should be prescribed. The safety profile is relatively favourable in terms of
known long-term oncogenic risk. Normal serum PIIINP levels are much higher
in children and are therefore of little value in monitoring for hepatotoxicity.
With acknowledgements to Jonathan Barker, author of this chapter in the
1st edition, and Jean Ayer who reviewed this chapter from an international
perspective.
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Methotrexate
++Essential patient information
• The patient must understand and is able to comply with regular blood test
monitoring.
• The patient should seek urgent medical attention if they develop
symptoms of serious infection including fever, sore throat, breathlessness or
unexplained bleeding or bruising.
• Clear prescribing information is essential, especially when folic acid is
co-prescribed with MTX, to avoid confusion between these drugs.
• Patients who have not had chickenpox and come into contact with either
chickenpox or shingles should seek urgent medical advice.
• Patient should inform their doctor/pharmacist that they are taking MTX
before starting any new medication.
• To help improve the safety of MTX prescribing a ‘MTX treatment booklet’
is recommended for patients to keep a record of any dose changes and the
results of monitoring investigations.
++Further reading
Berends MA, Snoek J, de Jong EM, et al. Biochemical and biophysical assessment
of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the
presence and Fibroscan predicts the absence of significant liver fibrosis. Liver
Int 2007;27:639–45.
Chalmers RJ, Kirby B, Smith A, et al. Replacement of routine liver biopsy by
procollagen III aminopeptide for monitoring patients with psoriasis receiving
long-term methotrexate: a multicentre audit and health economic analysis.
Br J Dermatol 2005;152:444–50.
Dogra S, Mahajan R. Systemic methotrexate therapy for psoriasis: past, present
and future. Clin Exp Dermatol 2013;38:573–88.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management
of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the
management and treatment of psoriasis with traditional systemic agents.
J Am Acad Dermatol 2009;61:451–85.
Montaudié H, Sbidian E, Paul C, et al. Methotrexate in psoriasis: a systematic
review of treatment modalities, incidence, risk factors and monitoring of liver
toxicity. J Eur Acad Dermatol Venereol 2011;25(Suppl. 2):12–18.
National Institute for Health and Clinical Excellence. Psoriasis: the assessment
and clinical management of psoriasis. Clinical guidelines CG153. Issued: October
2012 http://guidance.nice.org.uk/CG153.
Pathirana D, Ormerod AD, Saiag P, et al. European S3-guidelines on the
systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009;23
(Suppl. 2):1–70.
Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic
accuracy of noninvasive markers of liver fibrosis in patients with psoriasis
taking methotrexate: a systematic review and meta-analysis. Br J Dermatol.
2014 Jun;170(6):1237-47.
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Mycophenolate
Mofetil
Joey L. Chong & Jane Setterfield
++Classification & mode of action
Mycophenolate mofetil (MMF) is a lymphocyte selective immunosuppressive
agent. It inhibits de novo purine synthesis via its active metabolite, mycophenolic
acid, a potent selective and reversible inhibitor of inosine monophosphate
dehydrogenase. Lymphocytes are critically dependent for their proliferation
on de novo synthesis of purines, whereas other cell types can use salvage
pathways. MMF thereby prevents the proliferation of T-cells, lymphocytes and
the formation of antibodies by B-cells. It may also inhibit leukocyte recruitment
to inflammatory sites.
MMF is used for the prophylaxis of acute organ transplant rejection and like
several other immunosuppressive agents developed for this use, it has been
found to be an effective treatment for various inflammatory dermatoses. The
appeal of MMF in dermatology is related to both its potential steroid-sparing
effects and its relative lack of toxicity.
++Indications & dermatological uses
MMF is licensed for use in combination with prednisolone or ciclosporin
(cyclosporine) for the prevention of acute kidney, heart and liver transplant
rejection.
It has been demonstrated to be of benefit in the treatment of many
inflammatory skin diseases, but its use is unlicensed due to lack of large
randomized controlled clinical trials. It may be used either as a monotherapy
or as a steroid-sparing agent and is generally well-tolerated with a relative lack
of toxicity compared with other immunosuppressive drugs. Examples include:
• Autoimmune blistering diseases: bullous pemphigoid, mucous membrane
pemphigoid, epidermolysis bullosa acquisita, paraneoplastic pemphigus,
pemphigus foliaceus and pemphigus vulgaris.
• Dermatitis: actinic dermatitis, atopic dermatitis and psoriasis.
• Connective tissue disorders: dermatomyositis, lupus erythematosus,
scleroderma.
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Mycophenolate Mofetil
• Vasculitides: pyoderma gangrenosum, Churg–Strauss syndrome, hypocomplementaemic urticarial vasculitis, microscopic polyangiitis, Wegener’s
granulomatosis.
• Graft-versus-host disease: acute and chronic variants.
• Granulomatous dermatoses including cutaneous Crohn’s disease and
sarcoidosis.
• Others: lichen planus, relapsing idiopathic nodular panniculitis.
++Formulations/Presentation
• 250 mg capsules and 500 mg tablets of MMF.
• Oral suspension (1 g/5 mL) and 500 mg vials of MMF for i/v injection.
• Mycophenolic acid 180 mg and 360 mg delayed release tablets.
In patients who are unable to tolerate the gastrointestinal side-effects of MMF,
mycophenolic acid delayed release tablets may be an alternative. Mycophenolic
acid 720 mg is approximately equivalent to 1 g of MMF, but unnecessary
switching should be avoided due to pharmokinetic differences.
++Dosages & suggested regimens
The usual starting dose of MMF in dermatological disease is 500 mg bd. If
there is no improvement after 1 month, doses are typically increased in 500
mg increments. The usual maintenance dose is 1 g bd, increased to a maximum
of 1.5 g bd if required. These are the doses commonly used in transplant
recipients, and for therapeutic effectiveness in skin diseases, similar dosages
are usually required.
Dose adjustment is required for patients with renal insufficiency. In those
with a glomerular filtration rate (GFR) of less than 25 mL/min, the maximum
dosage is 1 g twice a day.
++Baseline investigations & considerations
•
•
•
•
•
•
•
FBC (CBC) and differential WBC.
Urea, electrolytes and creatinine.
LFTs.
Hepatitis B & C serology.
HIV testing s.
Chest x-ray.
Pregnancy testing and effective contraception for females of
childbearing age.
• Thorough examination of skin to exclude malignancy and clinical
examination to detect lymphadenopathy, breast lumps or organomegaly.
• Ensure up-to-date cervical screening.
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MMF may be used with caution in patients with HIV and hepatitis B and C virus
infection, under close collaboration with other specialist medical practitioners.
The immunosuppressant action of MMF can reactivate hepatitis B and C as well
as worsen the immunosuppressive status of patients with HIV.
Flu and pneumococcal vaccination are recommended for people who are
on immunosuppressant medication. Ideally these inactive vaccines should be
administered at least 2 weeks before therapy is started.
Varicella zoster virus (VZV) vaccine (live attenuated) should be given to the
non-immune several weeks before starting MMF if treatment can safely be
delayed.
++Monitoring
FBC, urea, electrolytes and creatinine and LFTs should be monitored weekly for
4 weeks, then twice a month for 2 months and then monthly for the first year.
Thereafter, most clinicians would advise monitoring every 3 months provided
the patient has been stabilized on MMF.
It is recommended to stop or withhold treatment and contact initiating
specialist in the following situations:
• Total white cell count <4 × 109/L.
• Neutrophil count <2 × 109/L.
• Platelet count <150 × 109/L.
• Aspartate or alanine aminotransferase >2 × the upper normal limit.
• Hypogammaglobulinaemia.
++Contraindications
• Hypersensitivity to MMF or mycophenolic acid.
• Pregnancy and lactation (see below).
• Rare inherited deficiencies of the enzyme hypoxanthine-guanine
phosphoribosyl-transferase, such as Lesch–Nyhan and Kelley–Seegmiller
syndrome, as it exacerbates the underlying abnormality of uric acid
metabolism.
++Cautions
• Peptic ulcer disease (active or past history) and serious gastrointestinal
(GI) disease, due to risk of GI haemorrhage, ulceration and perforation
associated with MMF therapy.
• HIV and hepatitis B or C (see above).
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++Important drug interactions
Patients should be advised to check with pharmacists and treating physicians
before taking any prescribed or over-the-counter medication while on MMF.
• Antacids with magnesium and aluminium hydroxides: may impair MMF
absorption.
• Cholestyramine and bile acid sequestrants: may reduce the enterohepatic
circulation and efficacy of MMF.
• Rifampicin: may decrease MMF efficacy.
• Broad-spectrum antibiotics such as ciprofloxacin and amoxicillin plus
clavulanic acid: may reduce the efficacy of MMF due to alteration of GI flora
and reduced enterohepatic drug recirculation.
• Azathioprine: also inhibits purine metabolism with potential enhanced
toxicity.
• Aciclovir (acyclovir), valaciclovir (valacyclovir) and related antiviral drugs:
may increase mycophenolic acid plasma concentration as they compete for
renal tubular secretion so closer monitoring of blood counts is needed.
• Hormonal contraceptive efficacy may be reduced: see specific manufacturer’s
recommendations.
++Adverse effects & their management
MMF is generally well-tolerated with fewer nephrotoxic, hepatotoxic and
neurotoxic side-effects than other immunosuppressive agents.
• Gastrointestinal: the most commonly reported side-effects are GI and are
dose dependent, occurring in up to 20% of patients at doses of 2 g daily.
They include diarrhoea, nausea, vomiting, abdominal pain, anal tenderness,
and constipation. These are usually mild and rarely severe enough to
result in discontinuation of therapy. Diarrhoea and nausea may be
reduced by increasing the dose frequency of MMF. Serious adverse effects
include GI haemorrhage, perforation and peptic ulceration.
• Myelosuppression: these are mostly anaemia and neutropenia and are
usually mild, dose related, and reversible with discontinuation of therapy
or dose reduction. Abnormal neutrophil morphology may occur with a left
shift phenotype in the absence of infection.
• Urinary: these include dysuria, urgency, frequency, and sterile pyuria, as well
as haematuria and urinary tract infection.
• Infection: the risk of common and opportunistic infections is increased,
especially at high doses. This includes herpes simplex, herpes zoster and
staphylococcal skin infections in patients with atopic dermatitis and
tuberculosis, atypical mycobacterial infections and lower respiratory tract
infection/pneumonia.
• Carcinogenicity: animal studies have shown an increase in lymphoma;
use of MMF in transplant recipients is associated with an increased risk of
malignancy, especially lymphoma and lymphoproliferative disorders and
non-melanoma skin cancer. These are generally considered to be related
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to the duration and intensity of immunosuppression rather than a MMF
specific effect. However, MMF may also impair UVB-induced DNA damage
repair and apoptosis by immunosuppression independent mechanisms.
There have been few reports of malignancy in dermatology patients. Rare
cases of primary CNS lymphoma and Epstein–Barr virus (EBV) related B-cell
lymphoma of the CNS have also been reported in non-transplant patients.
++Use in special situations
Pregnancy (FDA Category D)
MMF should be avoided in pregnancy as an increased rate of first trimester fetal
loss and congenital malformations including cleft lip and palate, anomalies of
the distal limbs, heart, oesophagus and kidney have been reported. Animal
studies have shown reproductive toxicity at doses equivalent to and less than
clinical doses.
Females of childbearing age should have effective contraception prior
to commencing MMF therapy, during therapy and for 6 weeks following
discontinuation of therapy. MMF should not be initiated until a negative
pregnancy test has been obtained. Patients should be instructed to consult their
physician immediately should pregnancy occur, due to the risk of teratogenicity.
Lactation
Mothers who are taking MMF should not breastfeed. Animal studies have
shown that MMF is excreted in milk and although it is not known whether
this applies to humans, breastfeeding should be discontinued because of the
potential risk to the infant.
Children
MMF is licensed for use in children of 2 years and above after renal
transplantation, at dosages of 600 mg/m2 twice daily (maximum 2 g daily).
There are sparse data of the use of MMF in infants under 2 years. There are very
few reports of its use for skin disease in children. Treatment is not appropriate
in children with a body surface area less than 1.25 m2.
Elderly
Elderly patients (>65 years) may generally be at increased risk of adverse
reactions due to immunosuppression, especially infection and possibly GI
disease.
++Essential patient information
• Patients should be fully informed of the indications for therapy and the
unlicensed use of the drug.
• The need for close monitoring with blood tests especially during the
initiation phase of treatment should be emphasized.
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• Patients should be informed of the increased risk of common and unusual
infections and the need to seek urgent medical attention if they become
unwell with a high fever.
• The small increased risk of skin cancer must be discussed and the potential
risk of lymphoma.
• Females of childbearing age should be given advice on the teratogenic
risk in pregnancy and effective contraception advised before treatment is
commenced.
++Further reading
Behrend M, Braun F. Enteric-coated mycophenolate sodium. Tolerability profile
compared with myophenolate mofetil. Drugs 2005;65(8):1037–50.
Li J, Kelly R. Treatment of pyoderma gangrenosum with mycophenolate mofetil
as a steroid-sparing agent. J Am Acad Dermatol 2013;69:565–9.
Mydlarski PR. Mycophenolate mofetil: a dermatologic perspective. Skin
Therapy Lett 2005;10:1–6.
Orvis AK, Wesson SK, Breza TS Jr, Church AA, Mitchell CL, Watkins SW.
Mycophenolate mofetil in dermatology. J Am Acad Dermatol 2009;60:183–199;
quiz 200–2.
Strathie Page SJ, Tait CP. Mycophenolic acid in dermatology a century after its
discovery. Australas J Dermatol. 2015 Feb;56(1):77-83
Ming M, Zhao B, Qiang L, He YY. Effect of immunosuppressants tacrolimus
and mycophenolate mofetil on the keratinocyte UVB response. Photochem
Photobiol. 2015 Jan-Feb;91(1):242-7.
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Potassium Iodide
Genevieve Osborne
++Classification & mode of action
Iodine is an essential dietary mineral, required for the biosynthesis of
tri-iodothyronine and thyroxine by the thyroid gland. Deficiency of iodine
leads to ’endemic goitre’, intellectual and developmental disabilities, which
can be prevented by the routine addition of iodine to dietary salt in the form
of potassium iodide (KI) or potassium iodate (KIO3). KI was first isolated in
seaweed in the 19th century, and thereafter it was used to treat both thyroid
disorders and various dermatological and infective diseases. Its use then
dwindled until the 1970s when reports appeared of its benefit in treating the
neutrophilic dermatoses, erythema nodosum and nodular vasculitis.
KI is well-absorbed orally and distributed selectively into the thyroid gland.
It also distributes to a minor extent into the salivary glands, breast, choroid
plexus and gastric mucosa. It readily crosses the placenta and is distributed into
milk, and is excreted mainly in urine, with lesser amounts via the faeces, saliva
and sweat.
The exact mechanism of action of KI in inflammatory dermatological
diseases is not understood, but is thought to be immunomodulatory. KI
appears to be most effective in conditions where neutrophils predominate,
and it has been speculated that it suppresses the ability of the neutrophils to
generate toxic oxygen intermediates and inhibits neutrophilic chemotaxis. The
antifungal mode of action of KI has not yet been established. Activation of
macrophages may be involved. KI does not have any direct antimicrobial action
on Sporothrix schenckii. The spontaneous healing and the variability of the
clinical presentation of sporotrichosis support the idea that KI acts by altering
the immune response of the host in this infection.
++Indications & dermatological uses
KI is a thyroid-blocking agent and is licensed for the treatment of thyrotoxicosis.
It is used to protect the thyroid during therapy with radioactive iodine and may
also be given pre-operatively before partial thyroidectomy. It is also used as
emergency protection of the thyroid following accidental exposure to radiation.
Solutions of KI are used as expectorants to reduce the stickiness of mucous in
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chest complaints. It is not licensed for use in any dermatological disease. Although
benefit has been reported in several dermatoses, the level of evidence for these
is limited to small open studies or case reports. These indications include:
• Fungal infections, specifically cutaneous and lymphocutaneous sporotrichosis
and cutaneous cryptococcosis. These probably account for the main use
of KI worldwide, given its low cost compared with systemic antifungal
medication. Benefit has also been reported in other subcutaneous mycoses
such as phycomycosis, human pythiosis, Nocardia brasiliensis, cutaneous
cryptococcosis and rhinoentomophthoromycosis (rhinophycomycosis).
• Panniculitis: erythema nodosum, erythema induratum (nodular vasculitis).
• Neutrophilic dermatoses: Sweet’s syndrome, pyoderma gangrenosum.
• Miscellaneous: erythema multiforme, Behçet’s syndrome, disseminated
­granuloma annulare, Wegener’s granulomatosis.
++Formulations/Presentation
• 65 mg and 130 mg tablets.
• Aqueous solution in various concentrations, including saturated.solution of
KI (1000 mg KI/ml)
• Supplements containing much lower doses of KI (e.g. 150 µg) can be
obtained from health food shops.
++Dosages & suggested regimens
• Tablets have a bitter taste and should be swallowed whole with plenty of
water. Aqueous KI solution may be diluted with water, juice or milk and
drunk with a straw to limit dental staining. The daily dose may be divided
to reduce gastrointestinal (GI) side-effects. For inflammatory dermatoses,
a typical dose is 300 mg tds for 2–4 weeks. Remissions have been reported
within 2 weeks. Higher doses are used for fungal infections, 600–2400 mg
tds. Children typically take one-third to one-half of the adult dose.
++Baseline investigations & considerations/Monitoring
Baseline monitoring includes:
• Urea, electrolytes and creatinine.
• Thyroid function; thyroid autoantibodies.
During treatment:
• Thyroid function should be checked every 2 months.
• KI is a source of potassium ions so serum potassium should be monitored if
given with drugs known to cause hyperkalaemia.
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++Contraindications
•
•
•
•
•
•
•
•
Impaired renal function.
Iodine induced goitre.
Hyperkalaemia.
Iodine hypersensitivity.
Pregnancy.
Lactation.
Hypocomplementaemic vasculitis, dermatitis herpetiformis.
Tuberculosis.
++Cautions
• Drugs that cause hyperkalaemia (see below).
• Previous thyroid disease and/or positive thyroid autoantibodies
(multinodular goitre, Grave’s disease, autoimmune thyroiditis) increase the
risk of hypothyroidism as there is dysfunctional thyroid autoregulation.
• KI should be used with caution in patients with Addison’s disease, cardiac
disease, myotonia congenita or renal impairment.
• Acne may be aggravated.
++Important drug interactions
• Drugs that cause hyperkalaemia, including spironolactone, p
­otassiumsparing diuretics, angiotensin converting enzyme inhibitors and ciclosporin
(cyclosporine).
• Iodine containing drugs, e.g. amiodarone and thyroid inhibiting drugs
(lithium, possibly sulphonamides) as they may cause hypothyroidism.
++Adverse effects & their management
• Gastrointestinal adverse effects are common and usually mild to moderate.
They include nausea, vomiting, diarrhoea and epigastric pain. They are
often dose related and can be limited by slow and small dose increments.
Rarely, small bowel ulceration.
• Thyroid dysfunction: occurs due to loss of normal thyroid gland
autoregulation. Hypothyroidism is more likely the longer KI is taken and
when there is pre-existing thyroid disease; it arises due to inhibition of
thyroid hormone production by an excessive iodine supply (Wolff–Chaikoff
effect). This and is usually reversible. Thyrotoxicosis may also occur when
taking KI if there are pre-existing functional thyroid foci, e.g. multinodular
goitre (Jod–Basedow effect).
• Metabolic: hyperkalaemia and metabolic acidosis may cause confusion,
arrhythmias, weakness, paraesthesia.
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Potassium Iodide
• Iodism/KI poisoning usually occurs at high doses or after prolonged use
and may cause oral ulceration and soreness, lacrimation, sialorrhoea,
rhinorrhoea and blurred vision. The side-effects usually resolve within a few
days of discontinuing KI.
• Hypersensitivity: angioedema, urticaria, bronchospasm, pulmonary
oedema, headache, fever, arthralgia and vasculitis can occur.
• Dermatological (iododerma): pustular, cystic and acneiform reactions can
result. Ulcerating nodules and plaques appear more common where there is
co-existing systemic disease. Immunobullous diseases (dermatitis
herpetiformis and bullous pemphoigoid) may be exacerbated.
++Use in special situations
Pregnancy (FDA Category D)
KI should not be used in pregnancy (unless benefits outweigh risks) as it crosses
the placenta and will cause fetal goitre and hypothyroidism.
Lactation
KI is contraindicated as it is excreted in breast milk.
++Essential patient information
Patients should be instructed to discontinue treatment and seek urgent
medical attention if they develop features of iodism, hyperkalaemia, shortness
of breath, severe abdominal pain or dark stool.
++Further reading
Cabezas C, Bustamante B, Holgado W, Begue RE. Treatment of cutaneous
sporotrichosis with one daily dose of potassium iodide. Pediatr Infect Dis J
1996;15:352–4.
Cohen PR, Kurzrock R. Sweet’s syndrome: a review of current treatment
options. Am J Clin Dermatol 2002;3:117–31.
Costa RO, de Macedo PM, Carvalhal A, Bernardes-Engemann AR. Use of
potassium iodide in dermatology: updates on an old drug; Ann Bras Dermatol
2013;88(3):396–402.
Hassan I, Keen A. Potassium iodide in dermatology. Ind J Dermatol Venereol
Leprol 2012;78:390–3.
Morris Jones R. Sporotrichosis. Clin Exp Dermatol 2002;27:427–31.
Schulz EJ, Whiting DA. Treatment of erythema nodosum and nodular vasculitis
with potassium iodide. Br J Dermatol 1976;94:75–8.
Sterling JB, Heyman WR. Potassium iodide in dermatology: a19th century drug
for 21st century – uses, pharmacology, adverse effects, and contraindication.
J Am Acad Dermatol 2000;43:691–7.
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Woeber KA. Iodine and thyroid disease. Med Clin North Am 1991;75:169–7.
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Propranolol
Susannah Baron & Brid O’Donnell
++Classification & mode of action
Propranolol was the first successful beta-adrenoceptor antagonist (betablocker) to be used medically following its discovery by James Black in 1962.
It is a non-selective beta-blocker and has been widely used in cardiovascular
medicine to treat hypertension, angina and tachyarrhythmias. In 2008, reports
of its successful use in infantile haemangiomas emerged and propranolol is
currently used to treat haemangiomas that are either causing, or are likely
to cause, clinically significant impairment of function or lesions that could
lead to significant permanent disfigurement if untreated. Haemangiomas
of infancy are vascular tumours that undergo a proliferative phase followed
by stabilization and eventual spontaneous involution. The therapeutic
effectiveness of propranolol in this indication may relate to peripheral
vasoconstrictive actions and the reduced expression of pro-angiogenic factors.
++Indications & dermatological uses
Propranolol is licensed for use in cardiovascular disease, essential tremor and
migraine prophylaxis. Its use in the treatment of infantile haemangiomas has
been on an off-label basis until recently. In 2014, The FDA and EMA granted
marketing authorisation for a new oral solution of propranolol, Hemangiol®
for proliferating infantile haemangiomas. Its cost is considerably greater than
other oral solutions.
++Formulations/Presentation
Oral solutions of propranolol (which are of relevance for infants) are available
in several concentrations ranging from 1mg/ml-10mg/ml. Hemangiol® contains
propranolol hydrochloride 4.28mg/ml, equivalent to propranolol 3.75mg/ml.
++Dosages & suggested regimens
As yet, there are no nationally agreed guidelines, and practice may vary in
different centres of expertise.
The following regimen for off-label use of propranolol oral solution is
suggested:
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Initiation of treatment should take place in a hospital setting. Infants <3
months old should be admitted and those ≥3 months treated as a day case.
Treatment may require the guidance of a paediatric cardiologist.
Propranolol should be administered within 1 hour of the last feed or
immediately before feeding.
Starting doses of 1 mg/kg/d are given with close monitoring (see below)
and increased after 24 hours to a maintenance dose of 2 mg/kg/d. The daily
dosage is taken as three divided doses at least 6 hours apart.
Some clinicians delay increasing propranolol to 2 mg/kg/d until the second
week of treatment. Other experts advocate a high initial test dose of 1 mg/kg
of propranolol (this is a higher dose than will be given on discharge) for infants
≥3 months old.
Occasionally higher doses are required, these can be increased on a monthly
basis according to the infant's weight. The dose should not be increased by
more than 0.5 mg/kg/d without cardiovascular monitoring (BP and heart rate).
The recommended starting dose of Hemangiol® is 1mg/kg/day in two doses
at least 9 hours apart, increased to 2mg/kg/day for the second week and then
3mg/kg/day as a maintenance dose. It is specified for initiation in infants aged
from 5 weeks to 5 months and for a 6-month period.
The child should be reviewed within 6–8 weeks of starting treatment, then
every 3–4 months. The growth period of infantile haemangiomas may vary
considerably, so the age at which treatment can be stopped is highly variable,
and treatment may be required beyond the age of 1 year. Some physicians
taper propranolol over a 4-week period at the end of treatment (e.g. half the
dose for 2 weeks, then half again for 2 weeks then stop). Haemangiol® may be
stopped without dose decreases.
++Baseline investigations & considerations
• A thorough clinical history and full examination especially cardio-respiratory
system with heart rate, BP and pulse oximetry (SpO2.).
• Document family history of arrhythmias or maternal connective tissue disease.
• Clinical photography.
• Echocardiogram and ECG in selected patients (see Table 1).
• Capillary blood glucose.
• Referrals to ENT team for suspected airway haemangioma and
Ophthalmology team for peri-ocular haemangioma.
++Monitoring
• Observations at initiation of treatment.
• Heart rate and BP every 30–60 minutes for 4 hours after each dose and
before the next dose.
• Capillary blood glucose at 2 and 4 hours after each dose and before the
next dose.
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• For infants weighing less than 3.5 kg or with co-morbidities, it may be
appropriate to continue monitoring for 4 hours or longer at the initiation
of the treatment and when the dose is doubled.
TABLE 1 Investigations for children receiving propranolol
Investigation
Required for
Echocardiogram and ECG
Large haemangiomas (>10 cm in diameter)
>5 cutaneous haemangiomas or known liver haemangioma
History, symptoms or signs of cardiovascular disease, i.e.
heart murmurs, tachypnoea, dyspnoea, tachycardia, poor
weight gain, difficulties feeding, repeated respiratory infections, cyanosis, enlarged liver, excessive sweating, fatigue,
clubbing of the fingers
PHACES
ECG
If the HR is below normal for age:
newborns (<1 month old), <70/min
infants (1–12 months old), <80/min
children (>12 months old), <70/min
FBC (CBC)/urea and electrolytes/
glucose/LFTs/TFTs
Liver haemangiomas, PHACES, Large haemangiomas,
Bleeding haemangiomas, Failure to thrive
Abdominal ultrasound
>10 cutaneous haemangiomas, Very large haemangiomas
Lumbosacral segmental haemangiomas, Failure to thrive
MRI brain and neck
PHACES
MRI spine
Plaque haemangioma in lumbosacral area/perineum crossing
the midline or perianal haemangioma extending into gluteal
cleft
ECG: electrocardiogram; FBC (CBC): full blood count; HR: heart rate; LFT: liver function test; MRI:
­magnetic resonance imaging; PHACES: plaque/segmental haemangiomas of the head syndrome; TFT:
thyroid function test.
++Contraindications
Asthma, uncontrolled heart failure, bradycardia, hypotension, atrioventricular
(AV) block, sick sinus syndrome, severe peripheral arterial disease,
phaeochromocytoma.
++Cautions
• Hepatic and renal impairment, portal hypertension, diabetes mellitus,
bronchospasm, heart disease.
Referral for additional specialist advice is recommended for suspected airway
haemangiomas (otolaryngeal referral) and for periocular haemangiomas
and plaque/segmental haemangiomas of the head syndrome (PHACES)
(ophthalmological referral).
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Propranolol
++Important drug interactions
• Lidocaine containing medications: care should be taken with topical agents
containing lidocaine, including teething gels (Bonjela, Dentinox and Calgel),
as concurrent use of propranolol increases the risk of lidocaine toxicity.
• Salbutamol or any other selective beta-2-agonists: if bronchodilatation is
needed, ipratropium bromide (Atrovent) should be used.
• Cardiac medication may increase the risk of bradycardia and hypotension.
Expert advice and closer monitoring is required.
• Corticosteroids may Increase the risk of hypoglycaemia due to adrenal
suppression.
• Bile acid sequestrants (colestyramine, colestipol) may decrease propranolol
levels up to 50%
++Adverse effects & their management
• Common: cold hands and feet, peripheral vasoconstriction, gastrointestinal
disturbance (diarrhoea or constipation), decreased appetite, agitation,
sleep disturbance, sweating.
• Rare: bradycardia, hypotension and high output cardiac failure.
Bronchospasm may occur. Propranolol should be temporarily discontinued
during episodes of viral induced wheeze or chest infection.
• Propranolol should be discontinued during intercurrent illness associated
with restricted oral intake and if the infant is undergoing procedures
requiring fasting, due to the increased risk of hypoglycaemia.
With acknowledgements to Ilona Frieden who reviewed this chapter from an
international perspective.
++Further reading
Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe
haemangiomas in infancy. N Engl J Med 2008;358:2649–51.
Ravenscroft J, Thakker P, Wells L. Guidelines for treating infantile haemangiomas
with propanolol. Nottingham Children’s Hospital, May 2013.
Solman L, Murabit A, Gnarra M, Harper JI, Syed SB, Glover M. Propanolol for
infantile haemangiomas: single centre experience of 250 cases and proposed
therapeutic protocol. Arch Dis Child 2014;99(12):1132–6.
Starkey E, Shahidullah H. Propranolol for infantile haemangiomas: a review.
Arch Dis Child 2011;96:890–3.
Storch CH, Haeger PH. Propranolol for infantile haemangiomas: insights into
the molecular mechanisms of action. Br J Dermatol 2010;163:269–74.
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Psoralens
Gillian Murphy & Veronika Dvorakova
++Classification & mode of action
Psoralens are naturally occurring furocoumarins that are found in several
plant species. They appear to have a protective role against microbes, and
inhibit germination of seeds. These aromatic molecules strongly absorb
certain ultraviolet (UV) wavelengths (220–400 nm) and act as photosensitizers
when administered orally or topically. Synthetic psoralens have been used
therapeutically in dermatology since the 1970s in conjunction with UVA in
psoralen-UVA photochemotherapy (PUVA). Three psoralens are in use in
dermatology: 8-methoxypsoralen (8-MOP; Methoxsalen), 5-methoxypsoralen
(5-MOP; Bergapten) and 4,5,8-trimethylpsoralen (TMP).
Photochemical reactions involve the interaction of light or UV radiation with
a specific molecule or chromophore, which absorbs this radiation to induce
a photochemical reaction. The precise molecular structure of a chromophore
determines the wavelength of radiation absorbed, while the degree of tissue
penetration by such radiation regulates the depth at which the photochemical
reaction occurs. In PUVA, the chromophore is psoralen, which is distributed
throughout the skin by diffusion from dermal blood vessels or transdermally
following topical application. Since UVA readily penetrates the skin to the
region of the papillary dermis, the therapeutic effects of PUVA are maximal in
epidermal and superficial dermal skin pathologies.
Psoralens intercalate between DNA strands, favouring thymidine rich
portions of genome. Subsequent absorption of UVA leads to their photoreaction
with DNA, binding to both sides of the double-stranded helix (bifunctional
adducts) to produce interstrand cross-links that prevent DNA replication. PUVA
also induces reactive oxygen species formation, which leads to cell membrane
damage by lipid peroxidation. Skin infiltrating lymphocytes are suppressed by
PUVA, which may explain its therapeutic effects in cutaneous T-cell lymphoma
as well as inflammatory skin diseases. PUVA induces pigmentation by enhanced
proliferation of melanocytes, increased formation and melanization of
melanocytes and transfer of melanosomes to keratinocytes.
++Indications & dermatological uses
Psoralens are unlicensed drugs in the UK and Ireland. 8-methoxypsoralen is
approved for dermatological diseases by the USA FDA. The main uses of PUVA
therapy are as listed below
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Psoriasis
PUVA is effective in clearing guttate, plaque and palmoplantar psoriasis,
but thick plaques may be slow to respond. The overall efficacy is good with
approximately 60–70% of patients achieving a 75% reduction from baseline
Psoriasis Area and Severity Index (PASI 75) and disease remission may last
several months. Maintenance PUVA should be avoided in order to minimize
cumulative skin damage and carcinogenesis.
Idiopathic vitiligo
PUVA is usually reserved for patients with deeply pigmented skin (types V or VI).
Widespread small lesions, central body involvement and disease of recent onset
responds best, while acral vitiligo and bony areas generally respond poorly.
Progress should be documented with clinical photographs (at approximately
4-monthly intervals) and treatment discontinued once improvement has
ceased. In sunny parts of the world, application of topical psoralen creams
and use of natural sunlight in low doses is widely practised. Narrow band UVB
therapy has now superseded PUVA as the treatment of choice for vitiligo, as it
has similar efficacy, but induces a better quality of skin repigmentation.
Cutaneous T-cell lymphoma (CTCL)
PUVA is an effective treatment for early stage CTCL, and achieves high rates of
clearance and prolonged disease free intervals, although the long-term course
of the disease may be unchanged. It is also a useful adjunctive therapy for
late stage disease through reducing tumour burden in the skin and improving
quality of life for patients. Extracorporeal photophoresis involves the removal
of circulating white blood cells, their irradiation with UVA in conjunction with
8-methoxypsoralen followed by reinfusion into the patient. It is used in the
treatment of advanced CTCL in persons who have not been responsive to other
forms of treatment.
Other unapproved dermatological conditions that are commonly treated
with PUVA include:
• Atopic dermatitis (atopic eczema); this is more difficult to treat compared
with psoriasis and a higher number of treatments is often required.
• Photodermatoses (polymorphic light eruption, solar uticaria, chronic actinic
dermatitis): the mechanism by which phototherapy induces tolerance
to sunlight might involve hyperpigmentation and thickening of stratum
corneum as well as modulation of cutaneous immune response.
• Other dermatoses: PUVA is also used with variable effect in other
dermatoses such as lichen planus, generalized granuloma annulare, chronic
graft-versus-host disease, urticaria pigmentosa and nodular prurigo.
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++Formulations/Presentation
Two oral psoralens are currently available:
• 8-MOP (Methoxsalen) is available in two different 10 mg capsule
formulations:
• Oxsoralen-Ultra® soft gelatin capsules taken 1.5–2 hours prior to UVA
exposure for psoriasis treatment.
• Puvasoralen® hard gelatin capsules taken 2 hours prior to UVA exposure
for psoriasis and 2–4 hours prior to UVA in vitiligo treatment. If nausea
occurs the dose may be divided and extended to 4 hours before treatment
in both diseases.
These formulations should not be used interchangeably as the bioavailability
and photosensitization time course is significantly greater/earlier for soft
gelatin capsules.
A variety of other generic and branded topical formulations are available
globally.
• Oxsoralen® lotion 1%: used topically prior to UVA for treatment of vitiligo
(USA only).
• 1.2% 8-MOP lotion for dilution in bathwater to a final concentration of
2.6 mg/L for immersion (bath- or hand/foot-PUVA).
• 5-MOP (Bergapten) is available in 20 mg capsules taken 3 hours before UVA.
TMP (tripsoralen/trioxsalen) manufacturing has now been largely discontinued.
It is still used in Scandanavia for bath-PUVA and is available as a 5% solution
in ethanol (5 mg TMP in 100 mL ethanol) for dilution in water and immersion.
++Dosages & suggested regimens
8-MOP capsules should be taken at a specified time before UVA exposure (see
above). The timing of psoralen ingestion should be exact and the dosage based
on bodyweight (Table 1). The usual dosage is 0.6 mg/kg bodyweight, which can
be decreased to 0.4 mg/kg if necessary to relieve nausea or other side-effects.
Ideally, food should be avoided 1 hour before and after dosing, but it is usually
necessary to take with a light meal to avoid nausea. In this case, the type and
amount of food should be kept constant for the patient to avoid variations in
drug bioavailability.
In standard PUVA regimens, the initial UVA exposure should preferably be
determined on the basis of prior measurement of the minimal phototoxic dose
(MPD) rather than skin type as this allows more accurate and higher UVA doses
during the initial treatment phase. PUVA erythema peaks at 48–96 hours and
as a compromise MPDs are usually measured at 72 hours. PUVA treatments are
usually given twice weekly for psoriasis, and increases in UVA dose calculated
as a percentage of previous exposures, or rarely by intermittent MPD testing.
Treatment regimens vary for other dermatoses: smaller incremental doses of
UVA are used in the management of atopic eczema and CTCL, while low doses
of UVA are used in the prophylaxis of polymorphic light eruption.
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TABLE 1 Standard dosages of 8-methoxypsoralen for psoralen combined with
ultraviolet A (PUVA) treatment of psoriasis
Patient’s weight (kg)
(lb)
(mg)
<30
<66
10
30–50
66–110
20
51–65
111–145
30
66–80
146–175
40
81–90
176–200
50
91–115
201–250
60
>115
>250
70
When adding an oral retinoid to patients already receiving PUVA therapy,
the UVA dosage needs to be reduced by about 50%. It is best to recheck the
MPD to minimize the risk of burning as the effects of retinoids vary between
individuals.
5-MOP is administered at a dose of 1.2 mg/kg and its slower absorption
leads to less nausea.
Retinoid with UVA (RePUVA): RePUVA therapy involves combination of a
systemic retinoid with PUVA. It reduces the number of treatments needed
for disease clearance by about one-third, and the total UVA dose often by
more than half compared with conventional PUVA. The ‘synergistic’ action
accelerates desquamation of psoriatic plaques, reduces inflammatory infiltrate
and retinoids also provide chemoprevention against non-melanoma skin
cancer development. Treatment is initiated with oral retinoid approximately
10–14 days before starting PUVA. The starting dose ranges from 0.1 to 1 mg/
kg as retinoids are variably tolerated by the individual; most people tolerate
0.3–0.5 mg/kg.
Acitretin is currently the conventionally used oral retinoid, but isotretinoin
can be used instead if prolonged risk of teratogenicity is unacceptable.[
Eye and skin protection: Patients should avoid sun exposure for at least 8 hours
after psoralen ingestion. Eye protection with special protective goggles is
mandatory during UVA exposure and UVA absorbing wrap-around sunglasses
should be worn throughout daylight after psoralen ingestion. The sunglasses
should be marked UV400 (blocking all wavelengths below 400 nm). In view of
the high risk of PUVA induced genital skin cancer in males, genital protection
with a UV opaque garment is strongly recommended. Facial skin, if unaffected,
should also be covered during treatment, usually by means of a visor.
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Topical PUVA (bath, immersion or paint): UVA is administered immediately
after immersion for bath PUVA therapy, while an interval of 15–30 minutes
should be allowed between application of psoralen paint and UVA exposure. It
is preferable to oral PUVA in patients with hepatic dysfunction, gastrointestinal
disease where absorption is impaired (e.g. after ileostomy), cataracts or those
unable to comply with eye protection, to permit shorter irradiation times and
where drug interactions are anticipated. Bath PUVA and oral PUVA appear to
have similar efficacy in the treatment of psoriasis.
Special point
MPD testing should be repeated if patients are changed from oral to bath PUVA,
as bath 8-MOP therapy is approximately 5–10 times more photosensitizing
than the oral form. Severe burning may therefore result if the UVA dose is not
reduced during conversion from oral to bath PUVA.
++Baseline investigations & considerations
•
•
•
•
•
FBC (CBC).
Renal profile.
LFTs.
Antinuclear antibodies.
Ophthalmological investigation for patients at increased risk of cataracts.
++Monitoring
• FBC, renal profile and LFTs should be repeated 6–12 months after initiation
of therapy.
• During and particularly after protracted PUVA therapy (more than
150 treatments) patients should undergo regular full skin examination
for pre-cancerous and cancerous lesions, as well as receiving advice on
self-examination for new or changing skin lesions.
++Contraindications & cautions
The absolute and relative contraindications for PUVA are listed below according
to guidelines from the British Photodermatology Group and the American
Academy of Dermatology:
Absolute contraindications (British Photodermatology Group
Guidelines)
• Xeroderma pigmentosum.
• Gorlin’s syndrome.
• Hereditary dysplastic naevus syndrome.
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Psoralens
•
•
•
•
•
•
Systemic lupus erythematosus.
Dermatomyositis.
Trichothiodystrophy.
Bloom’s syndrome.
Cockayne’s syndrome.
Previous malignant melanoma.
Relative contraindications
• Major:
• Age <10 years.
• Previous or current non-melanoma skin cancer.
• Previous exposure to arsenic or ionizing radiation.
• Current pre-malignant skin lesions.
• Concomitant immunosuppressive therapy.
• Pregnancy.
• Porphyria.
• Minor:
• Age <16 years.
• Cataracts.
• Bullous pemphigoid.
• Pemphigus.
• Previous or concomitant treatment with methotrexate.
• Significant hepatic impairment.
• Previous internal malignancy.
As oral psoralens are metabolized in the liver, it is sensible to avoid their use in
severe liver disease, although they may be used in mild impairment. Sporadic
reports of hepatitis associated with PUVA treatment have been published.
In severe impairment the use of topical psoralens is recommended (bath or
lotion) because serum levels are low compared with oral therapy.
Renal excretion is the main route of elimination of psoralen metabolites; thus
oral PUVA can be used in patients with stable renal impairment in a reduced
dose, but preferably combined with MPD measurement prior to treatment, to
reduce the risk of burning. Bath PUVA is preferable in such circumstances.
Contraindications (American Academy of Dermatology Guidelines)
• Lupus erythematosus.
• Porphyria.
• Xeroderma pigmentosum.
Cautions
•
•
•
•
•
•
Patients with skin type I and II who tend to burn easily.
History of arsenic intake.
Previous treatment with ionizing radiation.
History of melanoma.
History of multiple non-melanoma skin cancers.
Any medical condition causing intolerance of heat or prolonged standing.
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• Severe liver disease.
• Pregnancy and nursing.
• Previous treatment with ciclosporin (cyclosporine) or methotrexate.
++Important drug interactions
• Photosensitizing concurrent drug treatment should be noted, and if started
after the onset of PUVA, MPD testing should be undertaken with appropriate
UVA dosing to prevent excessive phototoxic reactions. These include
retinoids, non-steroidal anti-inflammatory drugs (NSAIDs), fluoroquinolone
and tetracycline antibiotics, thiazide diuretics, griseofulvin, phenothiazines
and sulphonamides. Other interactions include:
• Coumarin anticoagulants may be displaced from binding sites by psoralens.
• Anticonvulsant therapy can result in low serum concentrations of oral
psoralens as a result of the induction of hepatic enzymes.
• Hepatic cytochrome 450 (CYP450) 1A2 is inhibited by systemic PUVA and
metabolism of theophylline and other CYP1A2 substrates may be affected
(including tricyclic antidepressants and propranolol).
++Adverse effects & their management
Acute adverse effects
• Nausea is a relatively common side-effect of oral psoralens and is usually
reduced by taking psoralens with food. A light low fat meal is recommended
as high fat diets can cause a significant decrease in psoralen absorption.
Rescheduling UVA treatment for later in the day or taking the dose of
psoralen in divided portions over a 30-minute period may help. Severe
nausea can be treated with a prescription antinausea medication or if
intractable, the psoralen dose may be reduced by 10 mg and UVA dose
increased proportionately. Nausea is less frequent with 5-MOP therapy
because of slower absorption.
• Erythema and burning may occur due to pronounced sensitivity to psoralen
or excessive UVA dosing. Early recognition and prompt treatment with
emollients, topical corticosteroids and oral NSAIDs may be helpful. If not
too severe, once the erythema has resolved PUVA might be restarted at a
lower UVA dose, using smaller increments.
• Pruritus may be either localized or generalized, and usually occurs in patients
receiving oral psoralens. It may rarely be severe and persistent and treatment
with topical and systemic steroids, emollients and antihistamines is often
unsatisfactory. The itch has a prickling quality and may persist for weeks
to months before eventually resolving. If PUVA is required thereafter, oral
5-MOP should be used. Generally, however, further PUVA should be avoided.
• Anaphylaxis is an extremely rare event.
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Psoralens
Chronic adverse effects
• Cutaneous photocarcinogenesis and photoageing are the most significant longterm complications of PUVA. A significant increase in squamous cell carcinoma
(SCC) is noted in patients exposed to more than 150 treatments and there is also
an associated increase in basal cell carcinoma. An increased rate of melanoma has
been reported with high cumulative doses of PUVA, but there may be a latent
period of many years and the relationship remains to be clarified. Ciclosporin
should be avoided in those with a history of PUVA treatment as this increases
the risk of SCC development.
• PUVA lentigines (stellate hyperpigmented macules) may develop in
fair-skinned individuals, particularly after a high cumulative number of
PUVA treatments. Other skin changes related to high exposure include
poikiloderma.
• Cataracts: the induction of cataracts is a theoretical risk but is virtually
unheard of in practice. The use of UVA protective goggles in the UVA cabinet
and the wearing of UV protective glasses on treatment days prevents this
potential side-effect, which dissipates after 24 hours. Protective glasses are
not needed after bath PUVA.
++Use in special situations
Pregnancy (FDA Category C)
Small studies did not reveal a higher rate of congenital malformations,
although there was an increase in low birthweight babies born to females who
received PUVA during pregnancy.
Lactation
There is a minor risk of transmission of psoralen in breast milk, with the
consequent slight possibility of induction of photosensitization in infants.
PUVA in all forms is therefore contraindicated during lactation.
Children
Oral psoralens should not be used routinely in children under the age of
12 years due to long-term risk of carcinogenicity. Treatment can be undertaken
in special circumstances with great caution.
++Essential patient information
Prior to starting PUVA it is recommended that written patient consent is
obtained. This should supplement careful verbal explanation and helps to
document that the patient has been informed of potential risks of treatment.
With acknowledgements to Daniel Creamer and John Hawk, authors of this
chapter in the 1st edition.
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++Further reading
British Photodermatology Group guidelines for PUVA. Br J Dermatol
1994;130:246–55.
Halpern SM, Anstey AV, Dawe RS, et al. Guidelines for topical PUVA: a report of
a workshop of the British Photodermatology Group. Br J Dermatol 2000;142(1):
22–31.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management
of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment
of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol
2010;62:114–35.
Stern R.S. The risk of squamous cell and basal cell cancer associated with
psoralen and ultraviolet A therapy: a 30-year prospective study. J Am Acad
Dermatol 2012;66(4):553–62.
Sweetman SC (ed). Martindale: The Complete Drug Reference, 36th edn,
London, Pharmaceutical Press, 2009;1605–1607, 1620.
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Rituximab
Melissa Saber & Richard W. Groves
++Classification & mode of action
Rituximab is a chimeric, murine–human monoclonal antibody of
immunoglobulin (Ig) G1 subclass directed against the B-lymphocyte specific
antigen CD20 expressed only by pre-B and mature B-cells. These include early
B-cells in the bone marrow, autoantigen specific B-cells, memory B-cells and
mature B-cells. Haematopoietic stem cells and plasma cells lack the CD20
antigen and are therefore not affected by rituximab treatment. The precursor
cells maintain their ability to regenerate the B-lymphocyte population and
Ig levels generally tend not to decrease significantly since plasma cells are
unaffected. CD20 is thought to regulate cell cycle initiation and differentiation
of the B-cell lineage and possibly functions as a calcium channel. Interestingly,
rituximab seems predominantly to affect autoantigen specific B-cells in
comparison to memory B-cells directed against microbial antigens, which
seem to be protected by their privileged location in bone marrow and solid
organs. The fragment antigen-binding (Fab) domain of rituximab binds to the
CD20 antigen on B-lymphocytes and the Fc domain recruits immune effector
cells that mediate B-cell lysis. Three mechanisms of B-cell depletion have been
proposed including complement dependent cytotoxicity, antibody dependent
cell-mediated cytotoxicity and induction of apoptosis. Thus, rituximab results
in a rapid and sustained depletion of circulating and tissue-based B-cells, which
can be maintained for at least 6–12 months. Recent data suggest that rituximab
may also affect T-cell function and might modulate autoreactive T cells and
production of T-cell cytokines.
The half-life of the monoclonal antibody in the peripheral circulation is
approximately 8 days. It is thought that non-specific degradation of rituximab
occurs in the liver, followed by renal excretion.
++Indications & dermatological uses
Rituximab has been widely used in the treatment of B-cell malignancies with
use in over a million patients. The licensed indications in the UK are:
• B-cell haematological malignancies: CD20 positive non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukaemia.
• Severe active rheumatoid arthritis.
• It is also approved by the FDA for the treatment of Wegener’s granuloma­
tosis and microscopic polyangiitis.
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Rituximab
Rituximab has also been reported to be of benefit in the treatment of
several autoimmune diseases such as idiopathic thrombocytopenic purpura,
haemolytic anaemia, connective tissue diseases (systemic lupus erythematosus
[SLE], dermatomyositis, Sjögren syndrome) and systemic vasculitis. Its main
use within dermatology has been in the treatment of immunobullous skin
disorders, which is off label.
Patients suffering from immunobullous skin diseases who have failed
conventional immunosuppressive therapy (systemic corticosteroid with
other immunosuppressive agents) or have developed intolerable sideeffects from these drugs may benefit from rituximab. The most common
disease that has been treated is pemphigus vulgaris, and high response
rates have been reported, mostly when used in conjunction with concurrent
immunosuppressive medication. There have also been several case reports
and studies reporting effectiveness in pemphigus foliaceus, paraneoplastic
pemphigus, mucous membrane pemphigoid, epidermolysis bullosa acquisita
and bullous pemphigoid.
Other dermatoses that have been reported to respond to rituximab
include atopic dermatitis, chronic graft-versus-host disease, cutaneous lupus,
cryoglobulinaemia and cutaneous B-cell lymphoma.
++Formulations/Presentation
Rituximab is given by i/v infusion and is available as follows:
• Vials of 10 mL containing 100 mg of rituximab (packs of 2 vials).
• Vials of 50 mL containing 500 mg of rituximab (pack of 1 vial).
++Dosages & suggested regimens
The licensed dosing regimens in the UK for rituximab are as follows:
• Weekly infusions of 375 mg/m2 for 4–8 consecutive weeks, as a single agent
or in combination with chemotherapy (NHL regimen).
• Two infusions of 1000 mg given 2 weeks apart (rheumatoid arthritis
regimen).
In the initial reports of immunobullous disease treatment, the NHL regimen was
used, but the rheumatoid arthritis regimen is generally favoured nowadays.
Rituximab should be administered under close supervision in a setting
with full resuscitation facilities. Since transient hypotension may occur during
infusion, consideration should be given to withholding antihypertensive
medications 12 hours prior to and throughout infusion with rituximab. Treatment
with paracetamol (acetaminophen) and H1-antihistamines is recommended
before and throughout each infusion to reduce the risk of infusion reactions.
Pre-medication with corticosteroids may also be considered in order to reduce
the frequency and severity of infusion related reactions. Patients should receive
100 mg i/v methylprednisolone to be completed 30 minutes prior to each infusion.
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Patients with pre-existing cardiac conditions such as angina and arrhythmias
or patients who develop clinically significant arrhythmias should undergo
cardiac monitoring during and after subsequent infusions of rituximab.
For the first infusion, rituximab should be administered at an initial rate of
50 mg/h. If hypersensitivity or infusion related events do not occur, this can be
increased in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.
If hypersensitivity or an infusion related event develops, the infusion should
be temporarily slowed or interrupted. The infusion can continue at half of the
previous rate upon improvement of the patient’s symptoms.
Subsequent infusions of rituximab can be administered at an initial rate of
100 mg/h, and increased by 100 mg/h increments at 30-minute intervals, to a
maximum of 400 mg/h as tolerated. No dose adjustment is required in elderly
patients (aged >65 years).
The onset of therapeutic effects in autoimmune bullous dermatoses is
usually 2–3 months after initiation, though responses as late as 12 months after
initiation of treatment have been reported. If disease relapses, further courses
of rituximab can be safely administered without an increased risk of adverse
effects. The manufacturers advise avoiding readministration within 4 months
of the last infusion.
Adjuvant systemic immunosuppressive drugs can be continued with
concomitant use of rituximab but dose reduction should be considered
to decrease the risk of infections and other adverse effects related to
immunosuppression.
Treatment of cutaneous B-cell lymphoma with intralesional injections of
rituximab is also reported to be effective.
++Baseline investigations & considerations
•
•
•
•
•
•
•
FBC (CBC) and lymphocyte subsets including B-lymphocyte count.
Urea, electrolytes and creatinine.
LFTs.
Ig levels.
Hepatitis B and C serology.
(HIV) testing.
Pregnancy test.
These investigations should be repeated before each subsequent course
of rituximab. Immunization status should be assessed before initiation of
rituximab and consideration given to vaccination if appropriate.
++Monitoring
•
•
•
•
FBC and lymphocyte subsets (B-cell count).
Ig levels.
Urea, electrolytes and creatinine.
LFTs.
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These should be checked 1 month after the last infusion, then every 3 months.
In pemphigus, serum desmoglein 1 and desmoglein 3 antibody levels
should be measured by indirect immunofluorescence and/or enzyme linked
immunosorbent assay (ELISA) before, 1 month after the last infusion, then
every following 3 months, as they reflect disease activity and can predict
relapse. In the majority of patients with pemphigus vulgaris the level of these
autoantibodies parallels disease activity and decrease 3–10 months after
treatment with rituximab. Rarely, clinical improvement occurs in the absence
of a significant fall in antibody titre.
Circulating B-lymphocyte levels usually recover before disease activity
relapses, but in some patients relapse may occur despite persisting B-cell
depletion.
++Contraindications
•
•
•
•
•
Hypersensitivity to rituximab or to murine proteins.
Progressive multifocal leukoencephalopathy (PML).
Live virus vaccines.
Severe active infection including active hepatitis B disease.
Severely immunocompromised patients.
++Cautions
• Severe heart failure (New York Heart Association Class IV) or severe uncontrolled cardiac disease.
• Patients with positive hepatitis B serology but no active disease should be
referred to a hepatologist for assessment prior to starting rituximab, for
advice on further management and monitoring.
++Important drug interactions
There are limited data on drug interactions with rituximab. It is unlikely that
rituximab affects the pharmacokinetics of drugs that are used in combination
with it.
• Concomitant use of other immunosuppressive or immunomodulatory drugs
can enhance the degree of immunosuppression and increases the risk of
severe infections.
• Patients may be immunized with non-live vaccines during treatment with
rituximab. However, the vaccine response may be attenuated.
++Adverse effects & their management
Rituximab is generally well-tolerated.
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• Infusion reactions are usually mild to moderate and occur within 30–120
minutes of infusion. They can present with fever, chills, headache, weakness, hypotension, nausea, dizziness, cough, pruritus and urticaria. The majority of reactions occur during the first infusion of rituximab and are less
frequent with subsequent infusions. The symptoms are reversible when the
infusion is discontinued and can usually be prevented by use of pre-treatment with antihistamines, corticosteroids and paracetamol. When infusion
reactions happen, treatment should be discontinued. If symptoms resolve,
the infusion can be restarted at a reduced rate (half of the flow rate). More
severe (occasionally fatal) infusion reactions have been reported rarely with
acute respiratory distress syndrome, myocardial infarction (MI), ventricular
fibrillation, cardiogenic shock and/or anaphylaxis. Stop the infusion immediately and start appropriate supportive management.
• Infections may occur due to immunosuppressive effects. The most common
are respiratory tract infections, urinary tract infections and nasopharyngitis.
Serious infections and fatal outcomes have been reported in patients treated for autoimmune bullous diseases with rituximab. In other indications,
severe opportunistic, bacterial and viral infections such as pneumonias, pyelonephritis, skin infections, sepsis and systemic varicella zoster virus infections have been fatal. Reactivation of hepatitis B may occur (see Cautions),
leading to fulminant hepatitis.
Skin disease severity and concomitant immunosuppressant therapy affect
the risk of severe infections. It is therefore advisable to try to reduce other
immunosuppressive drugs to the minimal effective dose. Data from patients
with primary cutaneous B-cell lymphoma suggest that the risk of infection is
less frequent when rituximab is used as a monotherapy.
• Progressive multifocal leukoencephalopathy (PML) due to reactivation of
latent JC virus has been reported in at least 50 patients treated with rituximab for lymphoproliferative disorders, rheumatoid arthritis or SLE. Most
cases were diagnosed within 12 months of treatment. Confusion, disorientation, motor weakness, diplopia, altered speech, dysphagia and ataxia
should raise suspicion for PML. Discontinuation of rituximab and urgent
neurological evaluation is advised.
• Hypogammaglobulinaemia has been reported in rare cases of children
treated with rituximab for pemphigus vulgaris and bullous pemphigoid as
well as in adults. Hypogammaglobulinaemia may be associated with severe
infections in patients treated with rituximab.
• Leukopenia, neutropenia and thrombocytopenia have been reported in
about 10% of patients. Closer monitoring of blood counts is indicated in
such cases. Late neutropenia may occur up to 6 months after therapy. The
mechanism of these reactions is unclear.
• Cardiac adverse effects such as angina, arrhythmia, heart failure and MI
have been reported, so close monitoring is required in patients with history
of cardiac disease.
• Other severe adverse effects include tumour lysis syndrome and renal failure in patients with NHL.
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• Severe mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens–Johnson syndrome, toxic epidermal necrolysis and vesiculobullous dermatitis) have been reported. In these situations immediate cessation of treatment is required.
It is not clear if there is an increased risk of malignancy relating to the
immunosuppressant actions of rituximab.
++Use in special situations
Pregnancy (FDA Category C)
IgG is known to cross the placental barrier and transient B-cell depletion and
lymphocytopenia have been reported in some infants born to mothers exposed
to rituximab during pregnancy. For these reasons rituximab should not be used
in pregnancy.
Females of childbearing potential should use effective contraceptive
methods during treatment and for 12 months following the last infusion.
Lactation
Maternal IgG is excreted in human milk and mothers should not breastfeed
while receiving rituximab and for 12 months following the last infusion.
Children
There are limited safety data for the use of rituximab in children, but uncontrolled
studies have shown effectiveness in idiopathic nephrotic syndrome and severe
rheumatic diseases. Transient and persistent hypogammaglobulinaemia have
been reported in rare cases of children with immunobullous diseases (see
above).
++Essential patient information
• Patients should be advised to seek prompt medical attention if they develop
signs or symptoms of infection.
• Patients should be informed of the potential risk of PML, though the
magnitude of risk is unclear for patients with immunobullous disease.
++Further reading
Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus
vulgaris with rituximab and intravenous immune globulin. N Engl J Med
2006;355(17):1772–9.
Daniel BS, Murrell DF, Joly P. Rituximab and its use in autoimmune bullous
disorders. Immunol Allergy Clin North Am 2012;32(2):331–7.
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Hertl M, Zillikens D, Borradori L, et al. Recommendations for the use of
rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin
diseases. J Dtsch Dermatol Ges 2008;6(5):366–73.
Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the
treatment of severe pemphigus. N Engl J Med 2007;357(6):545–52.
Schmidt E, Bröcker EB, Goebeler M. Rituximab in treatment-resistant
autoimmune blistering skin disorders. Clin Rev Allergy Immunol 2008;34(1):
56–64.
Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for
ANCA-associated vasculitis. N Engl J Med 2013;369:417–27.
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Sulfapyridine &
Sulfamethoxypyridazine
Eirini Mereki & Catherine Hardman
++Classification & mode of action
The sulfonamide (sulphonamide) antibacterial drugs, sulfapyridine (SP) and
sulfamethoxypyridazine (SMP) are structurally related to para-aminobenzoic
acid (PABA). Their antibacterial effects are related to competitive inhibition
of the bacterial enzyme dihydropteroate synthase, which plays a key role in
converting PABA to dihydrofolic acid (a precursor of folic acid). Folic acid is
required for the biogenesis of DNA and RNA synthesis in both bacteria and in
mammals.
Sulfonamides do not affect human cells by this mechanism, as they require
pre-formed folic acid. Enzyme inhibition is reversible, so sulfonamides have
bacteriostatic rather than bactericidal activity. They are rarely used as antibiotics
nowadays due to adverse effects and bacterial resistance.
SP was introduced in 1938 as M&B (May and Baker) 693 and was one of the
first generation of sulfonamide antibiotics before being followed by several
other related drugs. Shortly afterwards their effectiveness in treating noninfective skin disorders was recognized. The current main use of SP and SMP is
in inflammatory skin conditions mediated by activated neutrophils. They impair
neutrophil cytotoxicity by inhibiting myeloperoxidase activity and preventing
the formation of activated oxygen species, leading to anti-inflammatory
actions. It is thought the inhibitory effects on neutrophil function are similar
to those of dapsone (see Dapsone). They may also affect the protein moiety
of glycosaminoglycans leading to a reduction in tissue viscosity, oedema and
vesicle formation.
Sulfonamides are slowly and incompletely absorbed from the
gastrointestinal (GI) tract and do not undergo first-pass metabolism. They are
protein bound to variable degrees in the circulation and unbound sulfonamide
diffuses throughout the body especially to sites of inflammation. Sulfonamides
are metabolized to inactive compounds by hydroxylation and acetylation
in the liver, the latter varying with acetylator phenotype. Parent drugs and
their metabolites undergo renal excretion and some sulfonamides are actively
reabsorbed in the renal tubule. SP has a half-life of about 6–14 hours depending
on acetylator status and SMP is longer acting, with a half-life of 22 hours.
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++Indications & dermatological uses
The produce licence for SP and SMP has lapsed and they are now only available
on a named patient basis. The main use for these drugs is in the treatment of
immunobullous diseases:
• Dermatitis herpetiformis.
• Linear IgA disease, chronic bullous dermatosis of childhood.
• Cicatricial (mucous membrane) pemphigoid.
Dapsone is usually the treatment of choice for these conditions, but should
be used with caution in elderly patients, when its haemolytic effects may be
poorly tolerated especially in those with underlying cardiorespiratory disease
(see Dapsone). In such patients, SP or SMP are preferred options. Combination
therapy with two or three agents (dapsone, SMP and SP) is occasionally used
in patients with treatment resistant disease. It also reduces the risk of renal
toxicity from crystalluria (see Adverse effects & their management).
Other rarer uses of SP and SMP include pustular disorders such as subcorneal
pustular dermatosis, pyoderma gangrenosum, pustular psoriasis and cystic or
conglobate acne. There have also been reports of benefit in acrodermatitis continua,
erythema elevatum diutinum and angiitis as well as leukocytoclastic vasculitis.
The pro-drug sulfasalazine, which is licensed for the treatment
of inflammatory bowel disease, is broken down in the colon to form
5-aminosalicylic acid and SP.
++Formulations/Presentation
• SP is available as 250 mg capsules under the brand name ‘Concord 693’. It is
manufactured by Archemides Pharma UK Ltd.
• SMP is currently available as 500 mg tablets by HAUPT Pharma. It is
manufactured as an unlicensed product in Germany and imported by IDIS.
Both drugs should be protected from exposure to light.
++Dosages & suggested regimens
SP and SMP are used as second-line agents when treatment with dapsone has
failed or is contraindicated. They may be used in combination or with low dose
corticosteroid if monotherapy does not adequately control the disease.
In the treatment of adults with dermatitis herpetiformis (Table 1) a typical
starting dose of SP is 500 mg twice a day, increasing if needed up to 3 g daily
and according to dose related side-effects. In most patients the rash is controlled
within this dose range. The clinical response should be assessed within 2 weeks
and dosage adjusted as necessary. The maintenance dose should be the lowest
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dose that prevents disease breakthrough. This may require frequent adjustment
because of irregular absorption. With longer-term use, drug requirements
should fall as dietary measures become effective. With a strict gluten-free diet,
drug requirements usually diminish after an average of 8 months, but it usually
takes 2 years of a strict gluten-free diet before drug discontinuation is possible.
A partial gluten-free diet usually requires ongoing drug therapy.
SMP has a longer half-life, and the usual starting dose is 500 mg once daily,
increasing as above according to disease response up to a maximum daily dose
of 1.5 g.
Lower doses are used in the treatment of other pustular and immunobullous
diseases.
Both drugs should be taken with plenty of water and a high fluid intake is
recommended.
TABLE 1 Dosage schedule for the treatment of dermatitis herpetiformis
Dosage/day
Sulfapyridine
Sulfamethoxypyridazine
Initial dose
1g
500 mg
If good disease control
reduce to*:
0.5 g
500 mg on alternate days
If disease not controlled,
incrementally increase dose to:
3g
1g
Maximum dose
4.5 g
1.5 g
if control is maintained, reduce the dose further at 2–3 day intervals until breakthrough occurs.
Maintain at the dose required to prevent breakthrough.
*
++Baseline investigations & considerations
•
•
•
•
•
FBC (CBC).
Reticulocyte count.
Urea and electrolytes.
LFTs.
Glucose-6-phosphate dehydrogenase (G6PD) level in patients from ethnic
groups at risk of deficiency (see Dapsone).
• Urinalysis.
++Monitoring
• FBC and urinalysis at monthly intervals for the first 3 months and then every
3–6 months.
• Urea and electrolytes and LFTs: in the absence of specific advice a similar
monitoring schedule is reasonable, i.e. monthly for the first 3 months, then
every 3–6 months.
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++Contraindications
•
•
•
•
•
•
•
Pregnancy & lactation (see below).
Hypersensitivity to sulfonamides*.
Infants (<1 year).
Acute porphyrias.
G6PD deficiency.
Pre-existing anaemia or history of haemolytic anaemia.
Interstitial lung disease (SMP).
*The sulfonamide chemical moiety is present in a range of other
non-antimicrobial drugs including certain diuretics, sulfonylureas and
cyclo-oxygenase 2 inhibitors. However, the reactive arylamine group present in
sulfonamide antibiotics that is a cause of drug hypersensitivity is absent in other
non-antimicrobial sulfonamides, and the latter do not routinely need to be avoided
in patients with a history of hypersensitivity to sulfonamide antimicrobials.
++Cautions
Extra caution should be taken when SP/SMP is prescribed in the following:
• Liver dysfunction: use lower dose.
• Renal impairment: use lower dose.
• Blood dyscrasias: requires closer monitoring.
++Important drug interactions
SP and SMP bind to plasma proteins and may displace other protein bound
drugs, resulting in increased free levels of the displaced drug with potential
toxicity. Drugs affected include:
• Ciclosporin (cyclosporine).
• Clozapine (increased risk of agranulocytosis).
• Coumarin anticoagulants (warfarin).
• Methotrexate.
• Phenytoin.
• Procaine (amino ester) local anaesthetics.
• Sulfonylurea oral hypoglycaemic agents.
• Non-steroidal anti-inflammatory drugs (NSAIDs): sulfonamides may be
displaced from the binding sites by highly acidic drugs such as NSAIDs,
increasing the risk of toxicity.
• Zidovudine: hepatic metabolism and clearance may be inhibited by SP.
• Live typhoid vaccine: sulfonamides possess bacterial activity against
Salmonella typhi and may thus interfere with the immunological response
to live typhoid vaccine. Allow 24 hours or more to elapse between the last
dose of the antibiotic and live typhoid vaccine. SP is also an inhibitor of
cytochrome P450 2C9 and this may also contribute to interactions.
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++Adverse effects & their management
Adverse effects are uncommon with the low doses used in dermatology.
Sulfonamides undergo hepatic metabolism to inactive compounds and slow
acetylators appear to be at greater risk of severe adverse drug reactions. The
adverse effect profile of SP and SMP are similar.
• Haematological: adverse effects include blood dyscrasias (leukopenia,
agranulocytosis and aplastic anaemia), methaemoglobinaemia and
sulphaemaglobinaemia. These can usually be prevented by careful FBC
monitoring and early drug withdrawal. Haemolysis particularly affects those
with G6PD deficiency, but can occur with normal G6PD levels. Macrocytosis
may also occur without folate deficiency.
• Dermatological: urticarial/immediate type hypersensitivity reactions
and delayed type hypersensitivity reactions may occur. The latter include
severe cutaneous adverse drug reactions (Stevens–Johnson syndrome/toxic
epidermal necrolysis and hypersensivitity vasculitis). Appearance of any
of these necessitates immediate drug withdrawal. Milder adverse effects
include uncomplicated exanthems and fixed drug eruptions. Desensitization
may be considered in special situations in patients with milder rashes. It
has been successfully reported in patients with cystic fibrosis and human
immunodeficiency virus (HIV) who require antimicrobial sulfonamide
therapy. Photosensitivity has been reported with various sulfonamides, but
is rarely a clinical problem with SP and SMP.
• Gastrointestinal: nausea and vomiting, stomatitis (SP >SMP) and abdominal
pain are usually mild and may be helped by dose reduction. Nausea and
vomiting often settle as treatment continues, so immediate change of drug
dosage may not be needed. Enteric coated formulations may help if available.
• Hepatotoxicity: this ranges from mildly abnormal LFTs to severe
hypersensitivity hepatitis with jaundice, fever and rash. Abnormalities
usually occur within the first month of treatment, but later reactions have
been described so continued monitoring is important. Pancreatitis has also
been reported as an idiosyncratic reaction with SP.
• Renal and urinary: crystalluria and nephrolithiasis are commoner with
rapidly excreted sulfonamides (SP >SMP) and relate to a reduction in drug
solubility in the acidic pH of the urinary tract. They may be asymptomatic
or cause renal colic, haematuria, chronic or even acute renal failure. A daily
fluid intake of 2.5–3.5 L is recommended to maintain high urinary output.
Other measures that reduce crystal precipitation include alkalinization
of the urine and using triple sulfonamide combinations. Nephritis and
albuminuria have also been rarely reported.
• Endocrine: goitre and thyroid dysfunction have been reported with SP.
• Neurological: fever, headaches, dizziness and drowsiness may respond to
dose reduction. Paraesthesiae and motor neuropathy have rarely been
reported.
• Respiratory adverse effects that have been reported specifically with
SMP include pneumonitis, alveolitis and obliterative bronchiolitis. These
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are potentially serious complications and usually present with progressive
breathlessness and cough. Chest radiographs show diffuse interstitial
shadowing and a restrictive pattern is seen on lung function tests (reduced
FEV1 and FVC). A peripheral eosinophilia has been found in a minority of
cases and an underlying vasculitis has been implicated. Most cases have
occurred during prolonged drug administration. The condition generally
responds to drug withdrawal and oral corticosteroid therapy but rare
fatalities have occurred.
• Hypersensitivity myocarditis is one of the most serious adverse effects, and
presents with cardiac failure.
++Use in special situations
Pregnancy & pre-conception (FDA Category C)
SP has been shown to cause oligospermia and infertility in males. Sulfonamides
can cross the placenta and are relatively contraindicated in pregnancy,
especially in the last trimester due to potential neonatal toxicity.
Lactation
SMP is contraindicated. The use of SP is controversial: it is excreted into breast
milk at a concentration of 30–60% of that in maternal serum. Infants with
G6PD deficiency may develop haemolytic anaemia. Kernicterus is theoretically
possible but breastfeeding, according to the manufacturers, does not pose a
significant risk for the healthy full-term neonate. However, its use should be
avoided in pre-term, stressed, or ill infants.
Children
Both drugs have been used safely in a limited number of children, especially
for chronic bullous disease of childhood (childhood linear IgA disease) (Table
2). The usual recommendation is to use half the adult dose for SP or 15–60 mg/
kg/d. For SMP dosing is weight dependent as below (based on manufacturer’s
advice for Lederkyn®, the previous available formulation of SMP).
TABLE 2 Sulfamethoxypyridazine dosing in children
Age in years (approx
weight)
Initial SMP dose/day
Maintenance SMP
dose/day
1–3 (9 kg)
250 mg
125 mg
4–6 (18 kg)
500 mg
250 mg
6–10 (27 kg)
750 mg
375 mg
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++Essential patient information
• Patients should be advised to maintain a high fluid intake during treatment
to reduce the risk of crystalluria.
• Patients should report immediately any signs of bone marrow suppression
(bleeding, bruising, etc) or new rashes.
• Due to the possible risk of photosensitivity, patients taking sulfonamide
drugs should be advised to avoid excessive sun exposure.
With acknowledgements to Jonathan Leonard, author of this chapter in the
1st edition.
++Further reading
Caproni M, Antiga E, Melani L, Fabbri P. Guidelines for the diagnosis and
treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol
2009;23(6):633–8.
Fortuna G, Marinkovich MP. Linear immunoglobulin A bullous dermatosis. Clin
Dermatol 2012;30(1):38.
Ingen-Housz-Oro S. Linear IgA bullous dermatosis: a review. Ann Dermatol
Venereol 2011;138(3):214–20.
Ingen-Housz-Oro S, Bernard P, Bedane C, Prost C, Joly P. Linear IgA dermatosis.
Guidelines for the diagnosis and treatment. [Centres de référence des maladies
bulleuses auto-immunes. Société Française de Dermatologie]. Ann Dermatol
Venereol 2011;138(3):267–70.
Marsden RA, McKee PH, Bhogal B, Black MM, Kennedy LA. A study of benign
chronic bullous dermatosis of childhood and comparison with dermatitis
herpetiformis and bullous pemphigoid occurring in childhood. Clin Exp
Dermatol 1980;5(2):159–76.
McFadden JP, Leonard JN, Powles AV, Rutman AJ, Fry L. Sulphamethoxypyridazine
for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid. Br J
Dermatol 1989;121(6):759–62.
Paniker U, Levine N. Dapsone and sulfapyridine. Dermatol Clin 2001;
19(1):79–86.
Pfeiffer C, Wozel G. Dapsone and sulfones in dermatology: overview and
update. J Am Acad Dermatol 2003 Feb;48(2):308–9.
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Thalidomide
Elaine Agius & Robert P.E. Sarkany
++Classification & mode of action
Thalidomide (alphapthalimido-glutaramide) is a derivative of glutamic acid and
was first introduced in 1957 as a non-barbiturate sedative hypnotic. However, it
was withdrawn several years later when an association with severe congenital
abnormalities became clear. Thalidomide is a potent teratogen, and up to
12,000 newborn infants were affected, particularly with phocomelias. Interest
in thalidomide and its analogues has re-emerged in recent years as it has
significant anti-inflammatory, immunomodulatory and anticancer effects. It was
approved by the USA FDA for the treatment of erythema nodosum leprosum in
1998, then later by the FDA and European Medicines Agency for the treatment
of multiple myeloma. Thalidomide has orphan drug status. This provides
the incentive for a company to produce a drug for a rare medical condition
where a profit motive would otherwise be lacking. In the USA thalidomide is
prescribed under a mandatory registry, the System for Thalidomide Education
and Prescribing Safety (STEPS) and in Europe, it is dispensed according to the
Thalidomide Pharmion Pregnancy Prevention Programme.
Thalidomide has complex immunomodulatory effects which are not fully
understood. It has a direct suppressive effect on tumour necrosis factor (TNF)alpha synthesis, and reduces production of other cytokines such as interleukin
(IL)-6 and Il-12 and free radicals that may cause oxidative DNA damage. It also
activates apoptotic pathways and inhibits angiogenesis. New analogues of
thalidomide, lenolidamide and pomalidomide with greater anti-TNF activity
and reduced toxicity have been licensed for use in oncology.
++Indications & dermatological uses
Thalidomide is only licensed in Europe for the treatment of multiple myeloma.
It is widely used to treat leprosy reactions (erythema nodosum leprosum) and
licensed for this indication in the USA. It has also been reported to be of benefit
in a range of inflammatory skin diseases including:
• Actinic prurigo.
• Cutaneous lupus erythematosus.
• Erythema nodosom leprosum.
• Nodular prurigo.
• Pyoderma gangrenosum.
• Severe apthous stomatitis and Behçet’s syndrome.
• Graft-versus-host disease.
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•
•
•
•
•
•
Cutaneous sarcoidosis.
Erythema multiforme.
Kaposi’s sarcoma.
Lichen planus.
Uraemic pruritus.
Systemic mastocytosis.
++Formulations/Presentation
Thalidomide is available in 50 mg hard capsules.
++Dosages & suggested regimens
The onset of action is slow, and therapeutic effects may take several months
except in cases of resistant oral ulceration, where a more rapid response is
typical. Dosing for dermatological conditions is usually in the range of 50–150
mg per day taken at bedtime. It is advisable to initiate treatment at a low dose
for the first 3 months and titrate the dose upwards if tolerated. Slow relapse
usually occurs over a period of months following drug withdrawal, though longterm remission after discontinuation has been reported in subacute cutaneous
lupus erythematosus.
++Baseline investigations & considerations
Disease severity should be documented with clinical score if available and
dermatology life quality index (DLQI) and a full medical history taken to assess
history and risk factors for cardiac disease, thromboses and neuropathy, in
addition to the following:
• FBC (CBC).
• Urea, electrolytes and creatinine.
• LFTs.
• Thyroid function tests (TFTs).
• Coagulation screen (INR, activated partial thromboplastin time [APTT] and
derived fibrinogen).
• Nerve conduction studies.
• Pulse rate, BP and weight.
• Contraception and pregnancy prevention programme (including pregnancy
test) (Table 1).
• Prescription authorization form (Thalidomide Pharmion Pregnancy Prevention
Programme).
• Immunization with live vaccines (4 weeks) and inactive vaccines (2 weeks)
prior to commencing treatment. Patient may have flu vaccine while taking
thalidomide.
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TABLE 1 Contraception and pregnancy prevention programme for thalidomide
FEMALE PATIENTS OF CHILDBEARING POTENTIAL
Counselling: ensure the patient understands the teratogenic risk and
the absolute requirement for a reliable form of contraception without
interruption for 4 weeks before starting, throughout the entire duration
of treatment and for 4 weeks after stopping
Assess capability to comply with effective contraceptive measures and
explain the need to consult rapidly if there is a risk of pregnancy
Explain the need to commence the treatment as soon as thalidomide is
dispensed following a negative pregnancy test
Explain the need and check that the patient agrees to undergo
pregnancy testing every 4 weeks
Contraception: one effective method of contraception for 4 weeks
before therapy: ovulation inhibitory progesterone-only pills, e.g.
desogestrel NOT a combined OCP since this increases the risk of
thromboembolism
Pregnancy testing: should be carried out once the patient has been on
effective contraception for at least 4 weeks, and on the same day that
the prescription is issued
Prescribing and dispensing: prescriptions must be limited to 4 weeks
of treatment
Pregnancy test, writing of prescription and dispensing of thalidomide
should be carried out all on the same day
The prescription is only valid for 7 days from the date it is written
Treatment initiation form (Thalidomide Pharmion Pregnancy
Prevention Programme Women of Childbearing Potential) signed by
patient
FEMALE PATIENTS OF NONCHILDBEARING POTENTIAL
Check that patient is either post-hysterectomy or 1 year post-menopause
Thalidomide Pharmion Pregnancy Prevention Programme Women of
Non-Childbearing Potential Treatment Initiation form signed by patient
MALE PATIENTS
Check that the patient understands the need for the use of a condom if
engaged in sexual activity with either a pregnant woman or a woman of
childbearing potential who is not using effective contraception
This applies during the treatment period and for 1 week after stopping
Treatment initiation form (Thalidomide Pharmion Pregnancy
Prevention Programme Male) signed by patient
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++Monitoring
• FBC (CBC), urea, electrolytes and creatinine and LFTs monthly for first 3
months then every 3 months thereafter.
• TFTs: repeat every 3 months.
• Nerve conduction studies: repeat every 6 months.
• Pulse rate, BP: repeat every 3 months.
• Pregnancy test: repeat every 4 weeks through treatment and 4 weeks after
discontinuing.
++Contraindications
• Hypersensitivity to thalidomide.
• Pregnancy.
• Females of childbearing potential unless all the conditions of the Pregnancy
Prevention Programme are met.
• Patients unable to fully adhere to required contraceptive measures.
++Cautions
• Patients with risk factors for myocardial infarction (MI), bradycardia,
atrioventricular (AV) block or cardiac failure.
• Existing peripheral neuropathy (may be aggravated).
• History or risk factors for thromboembolism, including smoking, hypertension
and hyperlipidaemia.
• The elderly are more susceptible to the adverse effects of thalidomide, so
lower dosages should be considered.
• Renal or hepatic insufficiency.
• Anaemia and/or cytopenias.
++Important drug interactions
There is evidence that thalidomide requires cytochrome P450 (CYP450)
catalysed biotransfomation to exert its pharmacological activity and that the
CYP2C subfamily may be primarily involved. The potential for clinically relevant
interactions with medicinal products appears to be low. Special precautions
should be taken with:
• Beta-blockers or anticholinesterase agents (e.g. neostigmine), due to
increased risk of bradycardia.
• Sedatives such as anxiolytics, hypnotics, antipsychotics, antihistamines,
opiate derivatives, barbiturates and alcohol, due to thalidomide’s sedative
effect.
• Drugs known to be associated with peripheral neuropathy (e.g. vincristine
and bortezomib).
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• Oral contraceptive pills and hormone replacement therapy, due to increased
risk of venous thromboembolic disease.
• Erythropoiesis stimulating agents, due to a higher risk of thromboembolic
reactions.
• Live vaccines since thalidomide is an immunosuppressant.
++Adverse effects & their management
• Teratogenicity: the risk of intrauterine death or severe birth defects,
particularly phocomelia, is extremely high. Thalidomide must not be used at
any time during pregnancy.
• Venous and arterial thromboembolic events: an increased risk of venous
thromboembolism (such as deep vein thrombosis and pulmonary embolism)
and arterial thromboembolism (MI and cerebrovascular events) has been
reported in patients treated with thalidomide, especially during the first 5
months of therapy. Although the majority of data are associated with its
use in patients with malignant disease (multiple myeloma), there have been
isolated cases reported in a non-cancer setting. Patients should be advised
to seek urgent attention if they develop shortness of breath or limb pain/
swelling.
• Cardiac: drug induced bradycardia and AV block, may present with
orthostatic hypotension, syncope and signs of cardiac failure. BP and pulse
should be monitored regularly.
• Neurological: peripheral neuropathy is a very common, potentially severe
effect as it may be irreversible. It generally occurs following long-term use
and the risk appears related to cumulative dosage and duration of therapy.
However, reports following relatively short-term use also exist, and symptoms
may also develop some time after treatment has been stopped. The typical
presentation is with symmetrical painful distal paraesthesias. The risk may
vary with disease and is higher in nodular prurigo and Behçet’s disease. It
may also be greater in females and the elderly. All patients require careful
monitoring for symptoms of neuropathy including pain, tingling, numbness,
abnormal co-ordination or weakness. Expert neurological assessment should
be sought if these symptoms develop.
• Sedative: somnolence/drowsiness is an expected effect, so medication should
be taken before bed. Patients should be advised about possible impairment
of mental or physical abilities for hazardous tasks such as driving or operating
machinery.
• Haematological: neutropenia, lymphopenia, thrombocytopenia and anaemia
may occur. If white blood cell count (WBC) is <3.5 × 109/L, neutrophils <2.0 ×
109/L, lymphocytes <0.5 0 × 109/L, platelets <150 × 109/L, then withhold drug
until discussed with a haematologist.
• Hepatitis: biochemical evidence of hepatocellular, cholestatic and mixed
abnormalities may occur, usually within the first 2 months of therapy.
Most reactions resolve with dose reduction or drug discontinuation.
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Closer monitoring is indicated in patients with pre-existing liver disease or
concomitant use of hepatotoxic medication.
• Cutaneous: severe adverse effects include angioedema, Stevens–Johnson
syndrome and toxic epidermal necrolysis. Immediate discontinuation is
indicated.
• Gastrointestinal: these include dry mouth and constipation.
• Endocrine: thyroid abnormalities have been reported rarely. Common
side-effects of thalidomide (bradycardia, oedema, weight gain) may be
indistinguishable from the symptoms of hypothyroidism, so biochemical
monitoring is recommended.
++Use in special situations
Pregnancy & pre-conception (FDA Category X)
• Thalidomide is absolutely contraindicated due to the high risk of
teratogenicity.
• Thalidomide is excreted in semen; males are advised not to father children
during treatment or for 1 month after the last dose.
Lactation
The safety of thalidomide in lactation is not established. Mothers taking
thalidomide should not breastfeed.
Children
Thalidomide has been used successfully in children, particularly in actinic
prurigo. It should only be considered if clinically necessary and after alternative
treatments have failed.
++Essential patient information
• Patients should be informed of the reasons for treatment and whether the
drug is being used for a licensed indication or not.
• It should be explained that the onset of action is slow and that benefit may
not appear until after 2–3 months’ treatment.
• All patients must be aware of the extremely high risk of teratogenicity with
thalidomide used in pregnancy or around conception by both males and
females.
• Patients must clearly understand the need for regular monitoring in order to
minimize the risk of adverse effects and are able to comply with this.
• Patients should be advised that they are at increased risk of thromboembolic
events and should seek urgent medical attention if they develop the
following symptoms and signs: calf pain, chest pain, shortness of breath,
haemoptysis.
• Patients should be told about common adverse effects including sedation
and peripheral neuropathy.
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• It must be explained that medication must not be shared with anyone and
that the patient should not donate blood/semen.
With acknowledgements to Alex Harris, author of this chapter in the 1st edition.
++Further reading
Anderson KC. Lenalidomide and thalidomide: mechanisms of action – similarities
and differences. Sem Hematol 2005;42(Suppl. 4):S3–S8.
Chen M, Doherty SD, Hsu S. Innovative use of thalidomide. Dermatol Clin
2010;28:577–86.
Cortes-Hernandez J, Torres-Salido M, Castro-Marrero J, et al. Thalidomide in the
treatment of refractory cutaneous lupus erythematosus: prognostic factors of
clinical outcome. Br J Dermatol 2012;166:616–23.
Fabi SG, Hill C, Witherspoon JN, Boone SL, West DP. Frequency of thromboembolic
events associated with thalidomide in the non-cancer setting: a case report and
review of the literature. J Drugs Dermatol 2009;8:765–9.
Paghdal KV, Schwartz R. Thalidomide and its dermatologic uses. Acta
Dermatovenerol Croat 2007;15:39–44.
Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK. Thalidomide: dermatological
indications, mechanisms of action and side-effects. Br J Dermatol 2005;153:
254–73.
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Tumour Necrosis
F­ actor Antagonists
Leena Chularojanamontri & Christopher E.M. Griffiths
++Classification & mode of action
The tumour necrosis factor (TNF) family is a group of 19 cytokines that can
produce inflammation, apoptosis, proliferation and angiogenesis. The best
known members of the TNF family are TNF-α and TNF-β.
TNF-α is often simply referred to as ‘tumour necrosis factor’. At a low
concentration in tissues, TNF-α has beneficial effects such as prevention of
infections, although it can lead to excess inflammation and organ injury at
high concentrations. As the name implies, TNF-α has antitumour properties and
plays a key role in induction of apoptosis as well as transduction of cell survival
signals. Pro-caspase-8 is a key regulator of TNF-α induced apoptosis, while
nuclear factor kappa B (NF-κB) is the major factor in TNF-α induced survival
signals. The role of TNF-α in the regulation of the apoptosis and proliferation
cascade indicates its potential for the treatment of malignancy.
TNF-β or lymphotoxin is derived from T lymphocytes and has a 50%
amino acid sequence homology, and binds to the same receptor as TNF-α. Its
biological significance is unclear. TNF-α is a key pro-inflammatory cytokine
that plays a central role in the pathogenesis of psoriasis, psoriatic arthritis and
many dermatological diseases. It is released as soluble (sTNF) and membranebound forms (transmembrane TNF; tmTNF). sTNF and tmTNF bind to distinct
receptors: TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75) leading
to activation of NF-κB, inflammation and cell apoptosis, respectively. TNF may
also drive keratinocyte proliferation in psoriasis.
The anti-TNF agents/TNF antagonists currently used in dermatology can be
divided into two groups: monoclonal antibodies (adalimumab and infliximab)
and soluble TNF receptors (etanercept). Although all three drugs inhibit TNF-α,
their structures and pharmacodynamic and pharmacokinetic profiles are
different.
Adalimumab is a fully human monoclonal immunoglobulin (Ig)G1 antibody
specific for TNF-α. It acts by blocking TNF interaction with the p55 and p75 cell
surface TNF receptors.
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Infliximab is a chimeric IgG1 human–murine monoclonal antibody (~25%
mouse derived protein). It binds and neutralizes both soluble and membranebound TNF-α, but not TNF-β.
Etanercept is a soluble TNF receptor protein consisting of the extracellular
portions of human TNFR2 (p75) linked to the Fc domain of human IgG1.
Recently, new TNF antagonists such as golimumab and certolimumabpegol have been approved for rheumatological diseases. Golimumab, like
adalimumab, is a fully human IgG1 antibody licensed for the treatment
of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
Certolizumab-pegol is a humanized anti-TNF Fab’ fragment conjugated to a
polyethylene glycol to prolong serum half-life, which facilitates once-monthly
dosing. It is approved for the treatment of rheumatoid arthritis. As these two
Adalimumab and infliximab bind to both sTNF and tmTNF, whereas etanercept
binds primarily to sTNF and TNF-β. All three biological agents act by: (i) blocking
TNF receptor mediated mechanisms and (ii) inducing tmTNF (reverse-signalling)
events. In addition, adalimumab and infliximab can fix complement, thereby
leading to antibody dependent cytotoxicity and can trigger T-cell apoptosis,
whereas etanercept lacks these actions. Thus, adalimumab and infliximab seem
to have a greater propensity to cause lymphocyte apoptosis compared with
etanercept.
++Indications & dermatological uses
TNF antagonists are approved for the management of psoriasis and are also
indicated for psoriatic arthritis.
The Psoriasis Area and Severity Index (PASI) is a widely used measure of
the clinical severity of psoriasis whereas the Dermatology Life Quality Index
(DLQI) (see Appendix 4) is a validated tool used to evaluate the impact of skin
disease on quality of life. In the UK, patient eligibility for treatment with TNF
antagonists is dictated by the National Institute for Health and Care Excellence
(NICE) eligibility criteria, which include:
• Chronic plaque psoriasis of at least 6 months’ duration.
• Documented failure to respond to and/or unsuitability for other conventional
systemic treatments.
• A PASI of ≥10, and a DLQI of >10 for adalimumab and etanercept; and a PASI
of ≥20 and a DLQI of >18 for infliximab.
• Both PASI and DLQI are calculated before and during treatment.
The definition of treatment response is either:
• PASI 50: a 50% or greater reduction from baseline PASI or % body surface
area where PASI is not applicable, and at least a 5 point reduction in DLQI.
• PASI 75: a 75% reduction from baseline PASI.
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TNF antagonists should be discontinued if patients do not achieve these
response criteria. According to NICE guidelines, the time point for reviewing
whether to continue therapy is at 16 weeks for adalimumab, and 12 weeks and
10 weeks for etanercept and infliximab, respectively.
These three TNF antagonists are also approved for the treatment of other
inflammatory diseases:
• Adalimumab for ankylosing spondylitis, Crohn’s disease and rheumatoid
arthritis.
• Infliximab for ankylosing spondylitis, Crohn’s disease, rheumatoid arthritis
and ulcerative colitis.
• Etanercept for ankylosing spondylitis and rheumatoid arthritis.
There are several skin diseases that have been successfully treated off-label
with TNF antagonists (Table 1).
TABLE 1 Off-label uses of tumour necrosis factor (TNF) antagonists in skin diseases
Skin diseases
Off-label uses
Granulomatous diseases:
sarcoidosis
granuloma annulare
necrobiosis lipoidica diabeticorum
adalimumab, infliximab
infliximab, etanercept
infliximab, etanercept
Neutrophilic dermatosis:
pyoderma gangrenosum
Sweet’s syndrome
subcorneal pustular dermatosis
adalimumab, infliximab
infliximab, etanercept
adalimumab, infliximab
Autoimmune blistering diseases:
bullous pemphigoid
pemphigus vulgaris
mucous membrane pemphigoid
infliximab, etanercept
infliximab
etanercept
Autoimmune connective tissue diseases:
lupus erythematosus
scleroderma
dermatomyositis
Behçet’s disease
infliximab, etanercept
infliximab, etanercept
infliximab, etanercept
adalimumab, infliximab, etanercept
Acute and chronic graft-versus-host disease:
infliximab, etanercept
Other inflammatory dermatoses:
pityriasis rubra pilaris
SAPHO syndrome
multicentric reticulohistiocytosis
toxic epidermal necrolysis
erythema annulare centrifugum
Hailey–Hailey disease
hidradenitis suppurativa
vasculitis
infliximab
infliximab, etanercept
adalimumab, infliximab
infliximab
etanercept
etanercept
adalimumab, infliximab
adalimumab, infliximab, etanercept
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Tumour Necrosis ­Factor Antagonists
Special point: Tuberculosis
It is estimated that nearly one-third of the world’s population is infected with
tuberculosis (TB). While most cases are in developing countries, there has been
a rise in the number of TB case in the UK and USA in recent years. Immigration,
human immunodeficiency virus (HIV) infection and the rise in multidrug
resistant TB are contributory factors.
Asymptomatic latent TB infection may be reactivated upon
immunosuppression and this is an important risk with anti-TNF therapy as
TNF-α plays a central role in the phagocytic activity of macrophages.
Post-marketing surveillance has indicated an increased risk of TB associated
with the monoclonal antibodies (infliximab and adalimumab) compared with
the soluble receptor, etanercept. The risk of reactivation of latent TB has been
estimated to be 12-fold greater with infliximab than etanercept, and all antiTNF agents may increase the proportion of newly acquired cases of TB that
progress to active disease.
There is a high rate of atypical clinical presentations of TB with these agents.
Extrapulmonary disease occurs in >50% of cases and disseminated/miliary TB
may be found. Careful screening for TB prior to starting therapy and ongoing
vigilance for newly acquired disease is therefore essential.
There are few data available on off-label uses of adalimumab as it is
relatively new compared with infliximab and etanercept. However, the efficacy
of adalimumab is expected to be more like that of infliximab than etanercept
due to a similar mechanism of action. Etanercept appears to be ineffective or at
best moderately effective in hidradenitis suppurativa, pyoderma gangrenosum,
sarcoidosis, Crohn’s disease and Wegener’s vasculitis, whereas infliximab
appears to be effective.
++Formulations/Presentation
• Adalimumab: a single-use, sterile, preservative-free solution of 40 mg
adalimumab in a pre-filled autoinjector pen device or a pre-filled glass
syringe for s/c administration.
• Infliximab: a freeze-dried powder in 100 mg vials for reconstitution with
sterile water for i/v infusion over a period of 2 hours; the drug should be
infused within 3 hours after reconstitution or within 24 hours if refrigerated.
• Etanercept: preservative-free, lyophilized powder in 10 mg and 25 mg
vials for reconstitution with 1 mL of sterile water for subcutaneous
administration, pre-filled syringe with 25 mg or 50 mg etanercept and 50
mg pre-filled autoinjector pen.
• All the drugs should be stored at 2–8°C and reconstituted prior to injection.
++Dosages & suggested regimens
Adalimumab is administered s/c at an initial dose of 80 mg once, then, after
1 week, 40 mg s/c every 2 weeks for maintenance therapy. Maximal disease
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response is achieved after 12–16 weeks. Approximately 50% of patients
achieve a PASI 75 response at week 12 with this regimen.
Etanercept is administered s/c at a dose of 25 mg twice weekly or 50 mg
once weekly throughout treatment. Studies have shown that 48%, 38% and
34% of patients treated with etanercept 50 mg twice weekly, 50 mg once
weekly and 25 mg twice weekly achieved PASI 75 at week 12. In two separate
randomized controlled trials 71% and 60% of patients taking 50 mg twice
weekly and 50 mg once weekly, respectively, achieved PASI 75 at week 24. Thus
the USA FDA has approved a dosage of 50 mg once or twice a week for the first
3 months, whereas NICE did not consider the twice weekly 50 mg dosage to be
cost-effective and does not endorse this regimen. Infliximab is given as a 5 mg/
kg i/v infusion repeated after 2 and 6 weeks, then every 8 weeks thereafter.
Continuous treatment with anti-TNF agents provides better disease control
than interrupted therapy, and there may be some loss of efficacy if treatment is
reintroduced after a drug holiday. Loss of efficacy correlates with development
of antibodies to TNF antagonists. Co-administration of low dose methotrexate
(5–7.5 mg once weekly) can reduce the incidence of formation of antibodies
to infliximab and sustain efficacy. In rheumatology, methotrexate is routinely
co-administered with anti-TNF therapy in the treatment of rheumatoid arthritis, and
infliximab is also used with methotrexate for psoriatic arthritis. Withdrawal of antiTNF therapy usually leads to a slow relapse of disease with no evidence of rebound.
Switching between biologics may be considered in patients who have
experienced poor results or adverse effects. Many patients have demonstrated
a good response to a second anti-TNF agent, but no firm conclusions on
sequential use are currently available.
++Baseline investigations & considerations
•
•
•
•
•
•
•
•
FBC (CBC).
LFTs.
Urea, electrolytes and creatinine.
Urinalysis.
Pregnancy test.
Hepatitis B virus, hepatitis C virus, HIV.
Chest x-ray.
TB evaluation should be carried out on all patients; this includes a detailed
medical assessment of past history of TB and possible exposure to those with
active infection.
The tuberculin skin test (TST) or Mantoux test is routinely used as a screening
test for latent TB infection in asymptomatic individuals. However, it has several
limitations including the need for repeated clinic visits at 48 and 72 hours, a
lack of specificity for Mycobacterium tuberculosis in those who have received
TB immunization (false positive) and attenuated responses in patients receiving
immunosuppressant therapy (false negative). Interferon-gamma release assays
(IGRAs) are a new generation of laboratory tests based on the measurement
of interferon-gamma (IFN-γ) release from sensitized T cells in response to
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M. tuberculosis specific antigens using enzyme linked immunosorbent (ELISA)
techniques. IGRAs may be the future gold standard in TB screening and have
reported sensitivities and specificities of 89% and 98%, respectively.
A TST or IGRA should be performed at baseline according to local guidelines.
The TST remains a useful test, but IGRA is recommended if the TST is ambiguous
and particularly when the patient is receiving immunosuppressive therapy.
++Monitoring
FBC, LFTs, creatinine, urinalysis, and pregnancy tests should be performed at
weeks 4 and 12 and thereafter every 3 months for adalimumab and etanercept.
Infliximab requires monitoring at weeks 2, 6 and prior to each infusion.
Further TB testing may be required according to clinical signs and risks.
NB: The response to IGRAs may be reduced in patients taking anti-TNF
therapy, so their usefulness is limited once patients have commenced therapy.
++Contraindications
•
•
•
•
Serious infection (e.g. hepatitis B virus infection).
Active TB.
Congestive heart failure (NYHA grade III or IV), due to a risk of exacerbation.
NYHA class I or II heart failure with ejection fraction < 50% by
echocardiography.
• Hypersensitivity to any component of the formulation.
• Pregnancy or breastfeeding.
• History of demyelinating disease/multiple sclerosis.
++Cautions
• Family history of multiple sclerosis or other demyelinating disease.
• Live vaccines.
• Psoralen with ultraviolet A (PUVA) >200 treatments (especially if followed
by ciclosporin [cyclosporine]).
• Malignancies or lymphoproliferative disorders.
• Hepatobiliary disorders.
• Hepatitis C.
In addition the following should be noted:
TNF antagonists should be avoided in patients with a history of multiple
sclerosis or other types of demyelinating disease because of reports of either
new onset or exacerbation of pre-existing multiple sclerosis.
Hepatitis virus: patients who are chronic carriers of hepatitis B should
not be treated with TNF antagonists due to the risk of viral reactivation. TNF
antagonists can be used in patients with hepatitis C infection with appropriate
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evaluation and monitoring during therapy. The best studied of these drugs in
the setting of hepatitis C infection is etanercept.
Vaccines: patients should not receive vaccinations with live or live attenuated
organisms within the 2 weeks prior to starting therapy, during and for 6 months
after discontinuation. Patients should avoid contact with children who have
received the live polio vaccine for up to 4–6 weeks after the vaccination.
Pneumococcal and influenza vaccinations are safe and are recommended.
Malignancies: it should be noted that patients with psoriasis have a higher
risk of lymphoma compared with the general population. Moreover, they
are also at an increased risk of developing skin cancer due to previous sun
exposure, and UV phototherapy, particularly PUVA. Therefore, patients with
prior PUVA therapy and intensive use of immunosuppressive drugs should be
evaluated for skin cancer before and during TNF antagonist therapy.
Asymptomatic latent TB may be reactivated by anti-TNF therapy and a
respiratory physician should be consulted for advice on therapy that must be
commenced prior to anti-TNF therapy. Patients should be instructed to seek
medical advice if signs/symptoms suggestive of a TB infection (e.g., persistent
cough, wasting/weight loss, low grade fever, listlessness) occur during or after
therapy with anti-TNF agents.
++Important drug interactions
• Increased immunosuppression is more likely to occur when TNF antagonists
are combined with other immunosuppressive drugs such as ciclosporin.
++Adverse effects & their management
• Adalimumab. The commonest side-effects reported are injection site
reactions, viral, candidal and bacterial infections, dizziness, headaches,
vertigo, gastrointestinal upset, musculoskeletal pain, rash, asthenia and
malaise. Injection site reactions (erythema, itching, pain, swelling and
haemorrhage) occur in 15% of patients but generally do not result in
discontinuation of therapy.
• Etanercept. The commonest side-effects are injection site reactions, allergic
reaction, headache and upper respiratory tract infection. Injection site
reactions are common but usually diminish with ongoing therapy and do
not relate to antibody development.
• Infliximab. Infusion reactions are defined as any adverse events occurring
during or within 1 hour after completion of the infusion. These reactions
are mild to moderate symptoms such as flushing, pruritus, chills, headache,
and urticaria. Mild to moderate reactions occur in 3–22% of patients with
psoriasis. Severe infusion reactions include anaphylactic reactions and serum
sickness-like reactions are rare. If mild to moderate infusion reactions occur,
treatment can usually be continued by decreasing the infusion rate or
temporarily stopping the infusion. Pre-treatment with oral antihistamines,
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paracetamol (acetaminophen) and/or glucocorticosteroids should be
considered for the future infusions. Serious infusion reactions seem to
occur more frequently with intermittent rather than continuous therapy.
The commonest side-effects are upper respiratory tract infection, headache,
elevated liver enzymes and infection. Elevation of liver enzymes is generally
transient and asymptomatic. Treatment can be continued in the majority
of cases with close monitoring. The following guidelines can be used with
respect to the elevation of aminotransferase:
• Continue treatment if values <3 times of normal upper limit.
• Treat with caution if values 3–5 times of normal upper limit.
• Stop treatment if values >5 times of normal upper limit.
Other rare but important adverse effects of TNF antagonists include the
following:
• Demyelinating disorders have been reported with all three TNF antagonists;
the risk appears small and partial or full recovery has occurred on
discontinuation.
• Malignancy has been reported in association with anti-TNF therapy including
solid tumours, non-Hodgkin’s lymphoma and malignant melanoma:
however, as many patients have been exposed to other immunosuppressant
therapies in the past, it is difficult to determine the true risk of malignancy
with TNF antagonists alone.
• Congestive heart failure is a contraindication to anti-TNF therapy, but
reports of it occurring de novo with anti-TNF therapy are rare.
• Drug induced lupus has been reported in association with anti-TNF
therapy; treatment should be discontinued if symptoms develop, but can
be continued in asymptomatic patients who develop positive antinuclear
antibodies (ANA).
• Paradoxical worsening or new onset of psoriasis: has been reported in
patients given anti-TNF therapy for non-dermatological indications, and
rarely, for psoriasis.
++Use in special situations
Pregnancy & pre-conception (FDA Category B)
Anti-TNF agents cross the placenta and both infliximab and etanercept have
been detected in the serum of infants born to mothers who received these
agents. Although the majority of cases of antenatal exposure have resulted in
birth of normal infants, there is inadequate safety data to recommend their use,
and females who receive anti-TNF agents should use effective contraception. If
pregnancy occurs, temporary withdrawal of treatment should be considered.
The manufacturers advise that females who have received anti-TNF therapy
should avoid pregnancy for variable time periods following cessation, notably
6 months with infliximab.
Limited data suggest that TNF antagonists can affect sperm motility but the
clinical relevance is unclear at present.
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Lactation
Breastfeeding should be avoided in patients receiving TNF antagonist therapy
although limited evidence indicates that if present in breast milk, levels will be
extremely low.
Children
Longer-term safety data are lacking. However, etanercept is licensed for the
treatment of severe chronic plaque psoriasis in children aged 8 years and older if
their disease is unresponsive to conventional systemic therapy or phototherapy
or they are intolerant of treatment. The dosing schedule is 0.8 mg/kg up to a
maximum dose of 50 mg once weekly by s/c injection.
++Essential patient information
• Patients should be informed of the risks and benefits.
• Patients should be monitored for early signs and symptoms of infection
throughout treatment.
• All patients should be fully assessed for active and latent TB before starting
therapy.
• All patients should be assessed for current and past history of malignancy
and/or any future risk of malignancy before starting and throughout
treatment.
• Patients should not receive live or live attenuated vaccination within 2
weeks before, during and for 6 months after discontinuation.
• Patients at risk for hepatitis B infection should be screened for hepatitis B
prior to starting TNF antagonist therapy.
• Pneumococcal vaccine and annual influenza vaccine are recommended
while patients are on therapy.
• Agents should be discontinued at least four half-lives prior to major
surgery (2 weeks for etanercept, 4–6 weeks for infliximab, 6–8 weeks for
adalimumab).
• Where a TNF antagonist therapy is used outside its indication, written
consent should be obtained from the patient.
With acknowledgements to Nicholas Blickenstaff who reviewed this chapter
from an international perspective.
++Further reading
Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology:
rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and
alefacept (Part 2 of 2). J Am Acad Dermatol 2007;56:e55–79.]
Hewitt RJ, Francis M, Singanayagam A, Kon OM. Screening tests for tuberculosis
before starting biological therapy. BMJ. 2015 Mar 5;350:h1060.
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Kim IH, West CE, Kwatra SG, Feldma SE, O’Neil JL. Comparative efficacy of
biologics in psoriasis: a review. Am J Clin Dermatol 2012;13:365–74.
Leman J, Burden AD. Sequential use of biologics in the treatment of moderateto-severe plaque psoriasis. Br J Dermatol 2012;167(Suppl. 3):12–20.
Pathirana D, Omerod AD, Saiag P, et al. European S3-Guidelines on the
systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009;23
(Suppl. 2):1–70.
Rustin MH. Long term safety of biologics in the treatment of moderate-tosevere plaque psoriasis: review of current data. Br J Dermatol 2012;167:3–11.
Semble AL, Davis SA, Feldman SR. Safety and tolerability of tumor necrosis
factor-α inhibitors in psoriasis: a narrative review. Am J Clin Dermatol
2014;15:37–43.
Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’
guidelines for biologic interventions for psoriasis 2009. Br J Dermatol
2009;161:987–1019.
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Ustekinumab
Rose Mak
++Classification & mode of action
Ustekinumab is the first licensed biological therapy inhibiting the action of
interleukin (IL)-12 and IL-23 for use in the treatment of moderate to severe
psoriasis. It is a fully human monoclonal antibody that binds with high
affinity and specificity to the p-40 subunit common to IL-12 and IL-23, thereby
preventing their binding to cell surface receptors and blocking their ability
to activate T-lymphocyte subsets (Figure 1). IL-12 and IL-23 are heterodimeric
cytokines derived from activated dendritic cells. IL-12 activates Th1 lymphocytes
(that produce tumour necrosis factor [TNF] and interferon-gamma) while IL-23
stimulates survival and proliferation of Th17 lymphocytes that appear to play a
key role in the pathogenesis of psoriasis.
The longer half-life of usketinumab (21 days) compared with TNF antagonists
allows extended intervals between dosing for maintenance therapy.
IL-12 and IL-23 neutralization
IL-23
IL-12
β2
2R
1
IL-
R
1
23
2Rβ
Ustekinumab
IL-
IL-1
Ustekinumab
1
Rβ
12
IL-
NK or T-cell
membrane
No signal
Indicates binding between ustekinumab to the p-40 subunit of IL-12 and IL-23
FIGURE 1 Mode of action of ustekinumab, which binds to the p-40 subunit common
to both IL-12 and IL-23, thereby inhibiting their binding to cell surface receptors and
subsequent activation of T-lymphocyte subsets (reproduced with kind permission of
Janssen Pharmaceuticals).
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++Indications & dermatological uses
Ustekinumab is licensed for the treatment of adults with moderate to severe
plaque psoriasis or active psoriatic arthritis. In the UK patient eligibility for
treatment is determined by the National Institute for Health and Care
Excellence (NICE) criteria which include chronic plaque psoriasis of ≥6 months’
duration; documented failure to and/or unsuitability for other standard
systemic treatments including ciclosporin (cyclosporine), methotrexate and
psoralen with ultraviolet A (PUVA); with a Psoriasis Area and Severity Index
(PASI) of ≥10 and a Dermatology Life Quality Index (DLQI) of >10.
The 2009 British Association of Dermatologists’ (BAD) guidelines for biological
interventions for psoriasis recommended that TNF antagonists were the firstline intervention for patients fulfilling criteria for treatment with biological
therapy, with use of ustekinumab reserved for patients who had failed TNF
antagonist therapy or where these agents are contraindicated. This reflected
the limited (1 year) safety data for usketinumab available at this time.
Ustekinumab may be beneficial in the treatment of palmoplantar psoriasis
but more data are needed to further evaluate its use in this condition.
++Formulations/Presentation
• Ustekinumab 45 mg solution in a 0.5 mL pre-filled syringe for s/c injection.
• The solution is clear to slightly opalescent, colourless to light yellow.
• The pre-filled syringe should be kept in the outer carton in order to protect
from light.
• Ustekinumab should be stored in a refrigerator (2–8ºC).
Prior to injection, the pre-filled syringe should be taken out of the refrigerator
and be left to stand in room temperature for about 30 minutes. This allows
the solution to come to a comfortable temperature for injection (room
temperature). Injection into areas of psoriasis should be avoided.
++Dosages & suggested regimens
• Patients ≤100 kg: 45 mg administered s/c at weeks 0 and 4, then every
12 weeks.
• Patients >100 kg: 90 mg administered subcutaneously at weeks 0 and 4,
then every 12 weeks.
It is recommended that treatment should be discontinued if there is inadequate
clinical response after 28 weeks. In practice, the onset of action is usually evident
within 2 weeks and a 75% reduction in PASI (PASI 75) occurs in over 60% of
patients at 16 weeks with sustained efficacy at 12 months. After withdrawal,
there is a slow relapse with no rebound and the efficacy on retreatment does
not appear to be reduced.
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Pharmacokinetic data have shown that in patients weighing more
than 100 kg there is a 55% greater clearance and a 37% greater volume of
distribution. Clinical trials also showed a reduced efficacy in patients >100 kg
using a standard 45 mg dosage, and this is the rationale for the use of higher
(90 mg) dosage in these individuals. Consideration of the higher dose may
be useful in patients weighing 90–100 kg who have failed to respond to the
standard dose regimen.
In the treatment of psoriatic arthritis, ustekinumab is licensed both as
monotherapy and in combination with methotrexate.
++Baseline investigations & considerations
•
•
•
•
•
•
FBC (CBC).
LFTs.
Serum creatinine.
Urinalysis.
Pregnancy test.
Hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV),
screening for tuberculosis (TB) including chest x-ray.
• Body weight.
++Monitoring
FBC, LFTs, serum creatinine, urinalysis, pregnancy test and bodyweight should
be performed at weeks 4 and 12 and every 3 months thereafter. Further testing
may be required according to clinical signs and risks.
Use in kidney disease
There are no available pharmacokinetic data on the use of ustekinumab in
patients with renal or hepatic impairment. Theoretically the kidneys only play
a relevant role in the catabolism and elimination of protein therapeutics when
the molecular size is below the cut off for glomerular filtration of ~60 kDa
(examples include interleukin-10, growth hormone, erythropoietin and
anakinra). Ustekinumab is a human IgG1 monoclonal antibody and like other
biological therapies, has a molecular weight of ~150 kDa, so its clearance is
unlikely to be affected by renal impairment. Limited case reports on the use of
other antibody mediated therapy such as cetuximab and rituximab suggest that
these agents are safe in renal impairment with no dose reductions required. The
FDA advised that renal impairment was unlikely to alter the pharmacokinetics
of monoclonal antibodies, and therefore renal impairment studies were not
required in the development program of this group of compounds (including
ustekinumab).
In addition, data from approximately 2000 ustekinumab-treated psoriasis
patients in the PHOENIX 1 and PHOENIX 2 phase three trials showed that the
creatinine clearance did not substantially alter the clearance of ustekinumab.
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++Contraindications
• Hypersensitivity to ustekinumab.
• Significant active infection.
• Pregnancy or breastfeeding.
++Cautions
• Due to the potential of biological therapies in increasing the risk of
infections and reactivating latent infections, ustekinumab should be used
with caution in patients with chronic infection or history of recurrent
infection, especially TB.
• Consider possible increased risk of malignancy.
• Provide age-appropriate immunizations prior to initiating therapy.
• Use caution in patients genetically deficient in IL-12, IL-23.
++Important drug interactions
No drug interactions have been reported thus far. In vitro, ustekinumab has no
effect on cytochrome P450 (CYP450) activities.
• Live vaccines should not be given concurrently with ustekinumab, and
should be withheld for at least 15 weeks after the last dose of ustekinumab;
medication can resume at least 2 weeks after live vaccinations.
• The safety and efficacy of ustekinumab in combination with other
immunosuppressants including biologics, or phototherapy have not been
evaluated.
++Adverse effects & their management
• The most common adverse reactions (>5%) are nasopharyngitis, headache
and upper respiratory tract infection. These are usually mild and treatment
can be continued.
• Injection site reactions are less common than with TNF antagonists, possibly
due to the infrequency of injections. They do not appear to be correlated
with the presence of neutralizing antibodies (that may reduce treatment
efficacy).
• Hypersensitivity reactions are usually mild and include rashes and
urticaria (<1 in 10 patients). Serious hypersensitivity reactions (anaphylaxis
angioeoedema) and Bell’s palsy are rare (<1 in 1000 patients). The needle
cover on the pre-filled syringe contains natural rubber latex and may cause
allergic reactions in individuals with latex allergy.
• Infections and reactivation of latent infections: serious bacterial, fungal and
viral infections such as herpes zoster and viral hepatitis have been observed
in patients receiving ustektinumab. If a patient develops a serious infection,
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ustekinumab should be withheld until the infection has resolved. Baseline
screening prior to commencing ustekinumab includes a careful evaluation
for TB and anti-TB therapy should be considered prior to initiating
ustekinumab in patients with past history of latent or active TB. Patients
should continue to be closely monitored for symptoms and signs of active
TB during and after ustekinumab treatment (see Tumour Necrosis Factor
Antagonists).
As ustektinumab is a newer therapy than TNF antagonists, it is important that
prescribers are vigilant to the possibility of unknown or long-term adverse
events. Serious infections, infections requiring antibiotics , malignancies and
major adverse cardiac events have been evaluated as adverse events of special
interest and have been found to remain stable for up to 5 years of treatment.
Biologics registries have been established in several European countries and
should provide increasingly robust data on the safety and efficacy of these
agents. Prescribers are strongly encouraged to enroll their patients into these
registries.
++Use in special situations
Pregnancy & pre-conception (FDA Category B)
The effect of ustekinumab on human fertility has not been evaluated but no
adverse effect on male fertility has been observed in animal studies.
Pregnancy should be avoided. Use of effective contraception during
treatment and for at least 15 weeks post-treatment is recommended. The
2009 BAD guidelines recommended that biologic agents should be avoided
and/or stopped in advance in females who are planning a pregnancy, and
biologic agents should be avoided so the fetus is drug free during the critical
developmental period of the first 12 weeks.
Lactation
It is unknown whether ustekinumab is excreted in human breast milk. Animal
studies have shown low level excretion of ustekinumab in milk, but it is
unknown if ustekinumab is absorbed systemically after ingestion. It is advised
that breastfeeding be discontinued during treatment and for 15 weeks after
treatment.
Children
Ustekinumab is currently unlicensed for patients under the age of 18 years old
and experience in younger patients is limited to case reports.
Elderly
No overall significant differences in efficacy or safety of ustekinumab have
been observed in patients aged 65 years old or over compared with younger
patients. However, due to declining immune function and the increased risk of
infections in the elderly population, caution is advised when treating this age
group with biologic drugs including ustekinumab.
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++Essential patient information
• Patients should be informed of the risks and benefits of therapy through
detailed discussion supplemented with written information.
• As ustekinumab is newer than other biologic therapies, the available safety
data are of shorter duration than TNF antagonists.
• Information on the risks of infections and guidance on vaccinations should
be provided and females of childbearing potential should be advised to
avoid pregnancy.
With acknowledgements to Nicholas Blickenstaff who reviewed this chapter
from an international perspective.
++Further reading
Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in
patients with moderate-to-severe psoriasis treated for up to 5 years in the
PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013;27:1535–45.
Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal
antibody for the treatment of psoriasis. N Engl J Med 2007;356(6):580–92.
Laws PM, Downs AM, Parslew R, et al. Practical experience of ustekinumab in
the treatment of psoriasis: experience from a multicentre, retrospective case
cohort study across the UK and Ireland. Br J Dermatol 2012;166:189–95.
McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, et al. Efficacy and safety of
ustekinumab in patients with active psoriatic arthritis: 1 year results of the
phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet
2013;382:780–9.
Nestle FO, Conrad C. The IL-12 family member p40 chain as a master switch
and novel therapeutic target in psoriasis. J Invest Dermatol 2004;123(6):xiv–xv.
Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’
guidelines for biologic interventions for psoriasis 2009. Br J Dermatol
2009;161:987–1019.
Yeilding N, Szapary P, Brodmerkel C, et al. Development of the IL-12/23
antagonist ustekinumab in psoriasis: past, present, and future perspectives.
Ann NY Acad Sci 2011;1222:30–39.
Zhu Y, Hu C, Lu M, et al. Population pharmacokinetic modelling of ustekinumab,
a human monoclonal antibody targeting IL-12/23p40, in patients with moderate
to severe plaque psoriasis. J Clin Pharmacol 2009;49:162–75.
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Vismodegib
Faisal R. Ali & John T. Lear
++Classification & mode of action
Vismodegib is the first in a new class of orally active anticancer drugs that
inhibit the hedgehog (Hh) signalling pathway by binding to smoothened
transmembrane protein (Smo) and blocking induction of Hh target genes. Many
of these genes are involved in cell proliferation, survival and differentiation.
Recent development of Smo inhibitors has led to the current investigation of
several drugs as therapy for a range of tumours.
The Hh signalling pathway plays a key role in the morphogenesis of the
epidermis and its appendages during embryogenesis and for self-renewal of
the skin and hair follicles throughout life. Mutations in PTCH1, the human
homolog of the Drosophila gene ‘patched’, which is a negative regulator of the
Hh pathway, have been found in both hereditary basal cell naevus syndrome
(Gorlin syndrome) and the majority of sporadic basal cell carcinomas (BCCs).
These result in an unregulated proliferation of basal keratinocytes and the
formation of tumours.
Vismodegib is absorbed after oral administration and slowly eliminated by a
combination of metabolism by cytochrome 450 (CYP450) 2C9 and CYP3A4/5 and
hepatic excretion of the parent drug. Only a small fraction is excreted renally. Its
terminal half-life after administration of a single dose is approximately 12 days.
++Indications & dermatological uses
Vismodegib was approved by the USA FDA in 2012 and by the UK MHRA in 2013
and is licensed for the treatment of adults with advanced BCC in the following
contexts:
• Symptomatic metastatic BCC.
• Locally advanced BCC inappropriate for surgery or radiotherapy.
Short-term studies (median duration of 6 months) have found that approximately
40% of patients with locally advanced BCC had a clinical response (reduction in
tumour diameter of >30%) and that there was clearance of the tumour in 20%
of patients.
In patients with metastatic BCC, approximately one-third showed evidence
of a clinical response.
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++Formulations/Presentation
• Hard capsules containing 150 mg vismodegib (Erivedge®).
++Dosages & suggested regimens
One capsule (150 mg) once daily. Capsules should be swallowed whole and
taken with water +/- food.
Tumour response should be gauged through serial measurements of tumour
diameter and the documentation of the presence of ulceration. Therapy should
be continued until disease progression or unacceptable side-effect profile. The
benefit gained and side-effect profile associated with continued treatment
should be regularly evaluated in each individual patient.
Adverse effects are common (see Adverse effects & their management,
below) and given its long half-life, interval dosing is being investigated as a
means to improve tolerability, though there are no formal guidelines for this.
The manufacturers advise that treatment may be interrupted for up to 4 weeks
if adverse effects are not tolerated.
Some BCCs continue to grow despite treatment (primary resistance) with
vismodegib and in other cases, there may be regrowth of the BCC after an
initial clinical response (acquired resistance). These may reflect mutations in
Smo which confer drug resistance, for example by decreased drug binding.
Vismodegib is not a curative treatment and in patients who respond, BCCs
have been found to recur within 3 months of stopping treatment. There is
interest in using this drug as neoadjuvant therapy, shrinking large primary
tumours prior to complex reconstructive surgery, but further studies are needed
to investigate this role.
++Baseline investigations & considerations
For females of childbearing potential, pregnancy testing within 7 days before
starting vismodegib treatment and commencement of the manufacturer’s
Pregnancy Prevention Programme (PPP) are imperative. The plan includes using
two forms of contraception prior to and during treatment and 24 months after
the last dose, including one highly effective method and a barrier contraceptive,
limiting prescriptions to 1 month’s duration and having monthly pregnancy
testing during treatment.
For males (including those with vasectomy) having sexual intercourse with
females of childbearing potential, counselling should be given of the need for
barrier contraception with spermicide throughout treatment and for at least
2 months after the last dose.
FBC, renal function and LFTs should be checked.
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++Monitoring
No specific recommendations currently exist. Intermittent monitoring of
routine blood parameters (FBC, LFTs, urea and electrolytes) may be advisable.
Females of childbearing potential should be part of the PPP, including monthly
pregnancy testing.
++Contraindications
• Hypersensitivity to the active substance/excipients.
• Pregnancy or breastfeeding.
• Females of childbearing potential who do not comply with the PPP.
++Cautions
Hepatic and renal impairment safety is not established. The manufacturers
advise close monitoring in patients with severe renal impairment and moderate–
severe hepatic impairment.
++Important drug interactions
• Antacids, proton pump inhibitors and H2-receptor antagonists may reduce
the solubility and bioavailability of vismodegib.
• CYP450 inducers (rifampicin, carbamazepine, phenytoin, St John’s wort
[Hypericum perforatum]) may reduce the effectiveness of vismodegib.
• Vismodegib is a substrate for the efflux transporter P-glycoprotein and the
metabolizing enzymes CYP2C9 and CYP3A4.
• P-glycoprotein inhibitors (e.g. macrolide antibiotics, verapamil, ciclosporin
[cyclosporine]), CYP2C9 inhibitors (amiodarone, fluconazole or miconazole)
and CYP3A4 inhibitors (incuding antiretroviral drugs, clarithromycin and
azole antifungal drugs) may increase systemic exposure to vismodegib and
the risk of adverse effects.
++Adverse effects & their management
Adverse effects are frequent and may be severe, leading to treatment
withdrawal.
• The most common side-effects of vismodegib are: muscle cramps (72%),
alopecia (64%) and taste disturbance (55%), including both abnormal taste
and loss of taste.
• Other frequent side-effects include: weight loss, fatigue, nausea, diarrhoea,
decreased appetite, constipation, arthralgia and vomiting.
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• Hepatitis with elevated transaminase and/or alkaline phosphatase levels has
been noted.
• Rebound of BCCs in hereditary basal cell naevus syndrome has been described
on discontinuing therapy.
• Squamous neoplasms have been reported to develop during treatment
with vismodegib including keratoacanthomas and moderate to highly
differentiated squamous cell carcinomas.
++Use in special situations
Pregnancy & pre-conception (FDA Category D)
Animal studies have shown irreversible loss of fertility after treatment with
vismodegib. Females taking vismodegib may become amenorrhoeic. Fertility
preservation strategies should be discussed with individuals who may wish to
have children after completing therapy.
Vismodegib is excreted in semen and male patients must use a condom when
having sex with a female of childbearing potential during treatment and for
2 months after the last dose.
Smo inhibitors including vismodegib are potent teratogens, causing severe
birth defects and embryofetal death. They are absolutely contraindicated during
pregnancy. In reality, the majority of female recipients will be beyond an age
of childbearing potential. However, for females with childbearing potential,
stringent precautions apply including a strict PPP. The manufacturers advise that
pregnancy must be avoided for 24 months after the final dose.
Lactation
Mothers must not breastfeed while taking vismodegib and for 24 months after
the final dose.
Children
Animal studies indicate a potential risk of short stature and tooth deformities in
infants and children and vismodegib should not be given to those under the age
of 18 years. This may be of relevance in hereditary basal cell naevus syndrome
where BCCs may first appear in early childhood.
Elderly
In clinical trials of vismodegib approximately 40% of patients have been over
the age of 65 years and vismodegib did not differ in terms of safety or efficacy
in this age group compared with younger patients.
++Essential patient information
• Patients and their carers should be advised that this treatment is for
symptomatic relief rather than curative; BCCs will likely recur if treatment
is discontinued.
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Vismodegib
• Patients and their carers should be advised of common adverse effects as
detailed above.
• Females of childbearing potential must comply with the manufacturer’s PPP
during treatment and at least 24 months following the final dose.
• Males (including those post-vasectomy) should use barrier contraception
with spermicide and must not donate semen while taking treatment and for
2 months after the final dose.
• Patients should not donate blood or blood products while taking vismodegib
and for at least 24 months after the final dose.
• Patients must inform their healthcare team should they or their partner
become pregnant while taking vismodegib, plan to become pregnant or
plan to breastfeed.
++Further reading
Ali FR, Lear JT. Systemic treatments for basal cell carcinoma (BCC): the advent of
dermato-oncology. Br J Dermatol 2013;169:53–7.
Chang Al, Solomon JA, Hainsworth JD, et al. Expanded access study of patients
with advanced basal cell carcinoma treated with the Hedgehog pathway
inhibitor, vismodegib. J Am Acad Dermatol 2014;70:60–9.
Electronic medicines compendium (eMC): Erivedge summary of ­product characteristics. http://www.medicines.org.uk/emc/medicine/28107/SPC/Erivedge+150+
mg+hard+capsules/. (Accessed on 7 March 2014.)
European Medicines Agency: European Public Assessment Report for Erivedge.
http://www.ema.europa.eu/ema/index
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in
advanced basal-cell carcinoma. N Engl J Med 2012;360:2171–9.
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Systemic Therapy
in Children
Susannah Baron
++Principles of treatment
Prescribing systemic therapies in children poses several challenges, not least
because many drugs are not licensed for use in the paediatric population. While
most children tolerate systemic medication well, neonates are at special risk of
adverse drug reactions due to their immature liver and renal function. Reliable
information on prescribing for children can be found in the British National
Formulary for Children (BNFC).
++Use of unlicensed & off-label medicines
When a pharmaceutical produce is granted market authorisation (‘product
license’), the terms of its use are clearly specified in the Summary of Product
Characteristics: dose, regimen, route of administration, patient population etc.
Use of the product outside these terms is said to be ‘off-label’. Much prescribing
in children is off-label, as the pharmaceutical companies do not usually have
sufficient data at the time marketing authorisation is granted. There is little
incentive to do so unless the drug is principally for use in children.
Off-label prescribing in children, should as far as possible be supported by
evidence of safety and efficacy. The use of the product outside the terms of its
license should be discussed with the child and their parents. Examples include
the use of ciclosporin in childhood psoriasis and azathioprine in atopic eczema.
The term ‘unlicensed’ refers to a product that does not have a license at all
and is a less common scenario. Such treatment will usually be initialed and
maintained in secondary or tertiary care. Secondary formulations of a product
(e.g. dilution or re-formulation) are also considered unlicensed.
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++Prescription, formulation & administration of
drugs in children
When choosing the best preparation for children, use one that is acceptable to
them and that fits in with their daily routine. Some flexibility should be allowed
in children to avoid waking them during the night so their night time dose may
be given at their bedtime.
For young children liquid preparations are frequently prescribed. Branded
oral liquid preparations that do not contain fructose, glucose or sucrose are
described as ‘sugar free’ and should be prescribed whenever possible to prevent
dental caries.
Some drugs are only available in solid dosage which can pose administration
problems for parents. It is important for parents to obtain the correct advice
from the dispensing pharmacist on crushing the tablets or emptying the capsules
into a suitable vehicle for administration.
Liquid preparations can be available in different strengths so it is imperative
when writing prescriptions to write clearly the drug dosage rather than the
amount to be given. Confusion can occur with oral solutions, e.g. methotrexate
and propanolol that are formulated in different strengths. This should
be discussed with the pharmacist and the parents and the same strength
formulation dispensed each time to avoid over- or under-dosage.
++Specific drugs
It is recommended that all drugs and dosages are checked in the BNFC or other
pharmaceutical database.
Acitretin (see Acitretin)
• Licensed for use in children in exceptional circumstances, e.g. severe
ichthyosis.
• Child 1 month–12 years: 0.5 mg/kg once daily with food or milk (occasionally
up to 1 mg/kg daily) to maximum of 35 mg daily.
• Child 12–18 years: for Darier’s disease 10 mg daily, for other conditions up
to 25–30 mg daily for 2–4 weeks then adjusted for response. Dosage may be
increased up to 75 mg for short periods in severe ichthyosis.
• Caution: growth should be monitored to detect premature epiphyseal
closure. Concomitant use of keratolytics should be avoided.
Acitretin is insoluble in water and light sensitive. A suspension may be
formulated from capsule contents for neonates and infants but care must
be taken that the suspension is dispensed in a dark bottle and not exposed
to light.
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Systemic Therapy in Children
Acne antibiotics (see Acne Antibiotics)
• Indications: infantile and childhood acne.
• In children <12 years: oral erythromycin is first-line treatment with oral
trimethoprim for resistant acne.
• In children >12 years: oral tetracyclines are the first-line systemic treatment.
Alitretinoin (see Alitretinoin)
Not recommended for use in children under the age of 18 years.
Antibiotics commonly used for skin infections (see Antibiotics
commonly used for skin infections)
Indications: impetigo/infected atopic eczema (atopic dermatitis).
Impetigo is common in young children and can be caused by Staphylococcus
aureus and beta-haemolytic streptococci. These bacteria may also be implicated
in infected flares of atopic eczema (atopic dermatitis). Flucloxacillin is the
treatment of choice for staphylococcal infections, with erythromycin an
alternative for penicillin-allergic children. Virulent and resistant communityonset staphylococcal disease has emerged worldwide associated with Panton–
Valentine leukocidin (PVL) cytotoxin. In the UK it is present in the majority of
community-associated methicillin-resistant S. aureus (MRSA). Clindamycin alone
or in combination with rifampicin may be used for PVL-positive S. aureus skin
infections in children. Advice should be sought from local microbiologists.
Antifungals (see Antifungals)
Oral azole antifungals (particularly itraconazole) and terbinafine are increasingly
being used in preference to griseofulvin as they have a broader spectrum of activity
and shorter treatment duration. Remember that immunocompromised children
are at particular risk of fungal infections. Table 1 provides detailed information
regarding age, formulation, appropriate dosages and licensing information.
TABLE 1 Formulation and licensing information for oral antifungals in children
Generic Name
Formulation
Information
Fluconazole
Capsules 50 mg, 150 mg,
200 mg
Oral suspension 50 mg/5 mL,
200 mg/5 mL
Unlicensed for superficial fungal
infections in children
Itraconazole
Capsules 100 mg
Oral liquid sugar free
10 mg/mL
Unlicensed in children under
12 years
Griseofulvin
Tablets 125 mg, 500 mg
Oral suspension 125 mg/5 mL
Licensed in children
Terbinafine
Tablets 250 mg
Unlicensed in children
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Systemic Therapy in Children
Tinea capitis is predominantly a complaint of pre-adolescent children;
infants are affected less commonly. Oral therapy is usually required in order
to eradicate the organism, alleviating disease symptoms quickly and safely
and to reduce transmission to others. The choice of drug will vary according
to the causative organism but as fungal culture may take up to 1 month it is
reasonable to start therapy immediately. Although griseofulvin is the only
drug licensed for the treatment of tinea capitis in children in the UK, newer
antifungal agents are gaining popularity, due to their greater cost-effectiveness
and safety. In the UK Trichophyton tonsurans is reported to account for 50–90%
of dermatophyte scalp isolates, whereas in Europe Microsporum canis remains
the most commonly involved organism.
Griseofulvin is more effective against Microsporum species than Trichophyton
species, and the latter may require prolonged therapy. The suspension is more
palatable for children, but has become expensive and may be difficult to source.
Terbinafine has much higher efficacy against Trichophyton species than
Microsporum species, and may be considered the treatment of choice for T.
tonsurans infection. A granule formulation which can be sprinkled over food is
licensed for use in children over 4 years in the USA.
Itraconazole is active against both Microsporum and Trichophyton species
and is widely used in many European countries. It is not licensed in children
under the age of 12 years in the UK. A liquid formulation exists.
UK guidelines suggest the use of griseofulvin or terbinafine as first-line
therapy, dependent on the organism suspected/isolated, with itraconazole used
as second-line therapy.
Fluconazole is licensed for use in the treatment of candidiasis in children of
all ages and exists in an orange flavoured liquid formulation. The antifungal
medications and dosage regimens suggested for use in children are outlined in
Table 2.
Onychomycosis is less common in children than in adults. The dominant
causative agents in this age group are T. rubrum, T. mentagrophytes and Candida
species. Griseofulvin is no longer recommended for paediatric onychomycosis
due to long treatment duration and lack of efficacy. Daily terbinafine and daily
or pulsed itraconazole have been shown to be well-tolerated in paediatric
populations, with faster response and higher cure rates than in adults due to
the faster growth of the nail plate in children.
Pityriasis versicolor may affect older children and usually responds to topical
therapy. If required it may be treated with oral itraconazole or fluconazole.
Widespread or intractable superficial candidiasis may require systemic
therapy. Fluconazole is licensed for use in mucosal and invasive Candida
infection in children of all ages. As stated above, itraconazole is not licensed for
use in children under 12 years.
Antihistamines (see Antihistamines)
Indications: urticaria, pruritus in atopic eczema, allergic rhinitis. If possible
prescribe sugar- and colour-free oral solutions. In practice, higher doses of oral
antihistamines than licensed dosages or those recommended in BNFC are often
used in chronic urticaria in children, as in adults.
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TABLE 2 Oral antifungal medication and dosage regimens for children
Generic
Name
Fluconazole
Itraconazole
Indication
Oropharangeal
candidiasis
Oral dose
12–18 years
Oral dose <12 years
50 mg daily for 7–14
<2 weeks: 3–6 mg/kg on day 1
days up to 100 mg daily then 3 mg/kg every 72 hours
2–4 weeks: 3–6 mg/kg on day
1 then 3 mg/kg every 48 hours
1 month–12 years: 3–6 mg/kg
on day 1 then 3 mg/kg for 7–14
days (max 100 mg)
Tinea corporis,
tinea cruris,
tinea pedis,
tinea manuum
1 month–18 years: 3 mg/kg
(max 50 mg) daily for 2–4
weeks (maximum duration
6 weeks)
Tinea capitis
1–18 years: 6 mg/kg (maximum
300 mg) daily for 2–4 weeks
Oropharyngeal
candidiasis
100 mg once daily for
15 days
1 month–12 years: 3–5 mg/kg
once daily (maximum 100 mg
daily)
Tinea corporis,
tinea cruris,
tinea pedis,
tinea manuum
Either 100 mg once
daily for 15 days in
tinea corporis and tinea
cruris, and 30 days for
tinea pedis and tinea
manuum, or 200 mg
twice daily for 7 days
1 month–12 years: 3–5 mg/
kg (maximum 100 mg) daily
for 15 days for tinea corporis
and cruris and 30 days for tinea
pedis and manuum
Onchomycosis
>50 kg 200 mg/d pulsed
for 1 week out of 4; 2–4
pulses may be needed
Pulsed dosing at 3–5 mg/kg 1
week out of 4; 2–4 pulses may
be needed
Tinea capitis
1–18 years: 3–5 mg/kg
(maximum 200 mg) daily for
2–6 weeks
Griseofulvin
Tinea capitis
>50 kg: 1 g/d (single or
divided dose) for 6–8
weeks
>50 kg: 15–20 mg/kg/d (single
or divided dose) for 6–8 weeks
Terbinafine
Tinea capitis
>40 kg: 250 mg/d for
2–4 weeks
<20 kg: 62.5 mg/d for 2–4
weeks
20–40 kg: 125 mg/d for 2–4
weeks
>40 kg: 250 mg/d for 2–4
weeks
Onchomycosis
Above dose for 6
weeks for fingernails
and 12 weeks for
toenails
Above dose for 6 weeks for
fingernails and 12 weeks for
toenails
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Antivirals (see Antivirals for HerpesViruses)
Indication: eczema herpeticum, an acute disseminated herpes simplex virus
(HSV) infection in children with atopic eczema. It is often associated with
systemic symptoms and should be treated with oral antiviral medication.
Aciclovir (acyclovir) is active against HSV. Tablets and suspension are not
licensed in children.
• Tablets, 200 mg, 400 mg, 800 mg.
• Dispersible tablets, 200 mg, 400 mg, 800 mg.
• Suspension, 200 mg/5 mL, 400 mg/5 mL.
• Child 1 month–2 years: 100 mg 5 times daily for 5 days.
• Child 2–18 years: 200 mg 5 times daily for 5 days.
Antimalarials (see Antimalarials)
Hydroxycloriquine is occasionally used for severe photodermatoses in childhood
at a dosage of 5–6.5 mg/kg (max 400 mg) once daily.
Biologics (see Tumour Necrosis Factor Antagonists)
The only biologic currently licensed for severe plaque psoriasis in children (aged
6 years and older) is etanercept. It is administered as a s/c injection of 800 µg/kg
(max 50 mg) once weekly for up to 24 weeks.
Corticosteroids (see Corticosteroids)
Prednisolone has predominantly glucocorticoid activity and is the corticosteroid
most commonly used orally in children with severe atopic dermatitis. There are
concerns regarding their potential to suppress growth due to the suppressive
action of glucocorticoids on the hypothalamic–pituitary–adrenal axis. This
suppression is greatest and most prolonged when the drugs are given at night
and least when given in a single dose in the morning.
Normal growth is allowed by 5 mg prednisolone/d for a child with 1 m2
surface area. Alternate day dosing may reduce growth suppression but can have
reduced therapeutic effectiveness against the disease being treated.
Courses of oral corticosteroids for skin diseases in children are usually
prednisolone 1–2 mg/kg in total and should be intermittent and short (5–7 days).
Prolonged courses increase susceptibility to infections and severity of infections.
Clinical presentations of infections may also be atypical or exacerbated.
Isotretinoin (see Isotretinoin)
Although unlicensed in children under 12 years old, isotretinoin has been
safely used in infantile acne and in younger children. Capsule contents are light
sensitive and insoluble in water. The author recommends mixing with a fatty
food such as peanut butter on toast in the dark! Severe infantile acne should be
managed by those with special expertise in paediatric dermatology.
• 1 month–2 years: 200 µg/kg daily.
• Child 2–12 years: 200–500 µg/kg increased if necessary to 1 mg/kg.
• Child 12–18 years: 500 µg/kg daily increased if necessary to 1 mg/kg.
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Immunosuppressive therapy
Before beginning systemic immunosuppressive medications in children, it
should be established if the child has had chickenpox. If in doubt the varicella
zoster virus (VZV) serology should be checked. Children who are not immune to
VZV are at risk of severe chickenpox when taking immunosuppressive therapy,
including prolonged corticosteroids. If exposed to chickenpox, advice should
be sought from the local microbiology department regarding post-exposure
treatment. If confirmed to have chickenpox infection or shingles the child will
need urgent specialist care and treatment.
Immunizations with live vaccines such as polio and rubella should be
avoided while children are taking systemic immunosuppressive drugs as the
immunizations may not be effective.
Most immunosuppressive agents are not licensed for use in the treatment
of skin disease in children including ciclosporin (not licensed under 16 years),
methotrexate and mycophenolate mofetil.
Special point: vitamin D supplementation
Children may have asymptomatic vitamin D deficiency. Furthermore, studies
have suggested that there may be an inverse relationship between the severity
of atopic dermatitis and vitamin D levels, with vitamin D supplementation
leading to a decrease in severity of disease. Therefore, in children with difficult
and severe eczema nutritional intake of vitamin D should be discussed with the
parents and levels checked if appropriate.
Simple nutritional vitamin D deficiency can be prevented by oral
supplementation with ergocalciferol (calciferol, vitamin D2) or colecalciferol
(vitamin D3) daily, using multivitamin drops or preparations of vitamin A and D.
With acknowledgements to Chin Gan and David Atherton, authors of this
chapter in the 1st edition.
++Further reading
Ameen M, Lear JT, Madan V, Mohd Mustapha MF, Richardson M. British
Association of Dermatologists’ guidelines for the management of onychomycosis.
Br J Dermatol 2014;17:937–58.
Feldstein S, Totri C, Friedlander SF. Antifungal therapy for onychomycosis in
children. Clin Dermatol 2014.
British National Formulary for Children. Pharmaceutical Press, London, 2014.
Downing HJ, Pirmohamed M, Beresford MW, Smyth RL. Paediatric use
of mycophenolate mofetil. Br J Clin Pharmacol 2013;75:45–59.
Fuller LC, Barton RC, Mohd Mustapha MF, Proudgood LE, Punjabi SP, Higgins EM.
British Association of Dermatologists’ guidelines for management of tinea
capitis. Br J Dermatol 2014;171:454–63.
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Systemic Therapy in Children
Lindell-Osuagwu L, Korhonen MJ, Saano S, Helin-Tanninen M, Naaranlahti T,
Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards
in Finland and review of the international literature. J Clin Pharm Ther
2009;34:277–87.
Mukattash T, Trew K, Hawwa AF, McElnay JC. Children’s views of unlicensed/
off-label paediatric prescribing and paediatric clinical trials. Eur J Clin Pharmacol
2012;68:141–8.
Terry D, Sinclair A. Prescribing for children at the interfaces of care. Arch Dis
Child Educ Pract 2012;97:152–6.
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Systemic Therapy &
Liver Disease
Rachel Westbrook & Mark Thursz
++Assessment of liver function
The prevalence of liver disease is increasing in the UK and worldwide and
assessment of hepatic function is essential before commencing any potentially
hepatotoxic drug. Pre-existing liver disease can be identified in the majority of
cases with a brief clinical history, examination and routine liver function tests
(LFTs) as below. Any abnormality requires further investigation to assess the
underlying cause and the extent of liver damage (fibrosis). This will allow an
informed decision to be made regarding the safety of a particular drug.
• Clinical history: alcohol consumption, illicit drug use, medication and family
history of liver disease.
• Clinical examination: stigmata of chronic liver disease (jaundice, spider naevi,
hepatomegaly, splenomegaly or ascites).
• Liver function tests:
• Aminotransferases: the enzymes aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) are present in hepatocytes and leak into
the blood when there is hepatocyte damage/inflammation.
• Alkaline phosphatase (ALP): elevations in ALP occur due to cholestasis (i.e.
failure of bile secretion or drainage) secondary to intra- or extrahepatic
causes. A raised ALP without gamma-glutamyl transferase (GGT) should
raise suspicion of bone disease. ALP levels are raised in pregnancy due to
production of the placental isoenzyme and the normal range is higher in
children.
• GGT: elevations in GGT occur in diseases of the liver and biliary system.
Causes include excessive alcohol consumption, cholestasis (intra- or
extrahepatic) and medication.
• Bilirubin: bilirubin is produced from the breakdown of erythrocytes in
the liver and reticuloendothelial system. Bilirubin is conjugated with
glucuronic acid in the liver and excreted in the bile. Rises in unconjugated
bilirubin are derived from extrahepatic erythrocyte breakdown, i.e.
haemolysis or defects in conjugation, e.g. Gilbert's syndrome. A rise
in conjugated bilirubin indicates hepatic disease and can be due to
hepatocyte damage, cholestasis or synthetic liver failure.
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•
Serum albumin: albumin is synthesized in the liver and thus a falling
albumin level may indicate synthetic liver failure; i.e. cirrhosis.
• Prothrombin time (PT): this is a marker of hepatic synthetic function due
to the short half-life of prothrombin. The PT may be prolonged in acute
liver injury and chronic liver disease (cirrhosis).
• Ultrasound scan: this non-invasive, safe and inexpensive investigation
should be undertaken in all patients with suspected liver disease. It
allows identification of parenchymal disease, biliary obstruction, portal
hypertension, vascular pathology and liver lesions.
If abnormalities of liver function are detected, specialist advice from a
hepatologist is essential prior to commencing a potentially hepatotoxic drug
to ensure the appropriate choice and dose of drug and adequate monitoring.
++Prescribing in patients with liver disease
Prescribing systemic dermatological treatment in patients with pre-existing liver
disease can present challenges as many of these drugs commonly cause liver
damage. The following factors should be considered:
• Is there an alternative, effective non-hepatotoxic drug?
• How severe is the underlying liver disease? Does the patient have hepatic
fibrosis/cirrhosis?
• Could the liver disease be treated/controlled prior to drug therapy?
• What is the effect of the drug on liver function? Does the drug have the
potential to worsen pre-existing liver disease? Is it a dose dependent or
idiosyncratic effect?
• What is the effect of liver disease on drug metabolism and dosage?
• How will the effect of the drug on liver function be monitored?
++Monitoring
More than 900 drugs have been reported to cause liver injury with manifestations
ranging from asymptomatic elevations in liver enzymes to fulminant hepatic
failure resulting in death or requiring liver transplantation. Drug induced
liver injury (DILI) is the most commonly cited reason for withdrawal of an
approved drug. Thus any prescriber must be vigilant in identifying DILI, as
early drug discontinuation can limit its severity. Hepatitic reactions (hepatocyte
inflammation) are usually associated with a rise in transaminases and cholestatic
drug reactions are usually associated with a rise in ALP and GGT levels, though
biochemical features often overlap.
As a general guide, patients commenced on a drug with an established
risk of idiosyncratic DILI, should undergo monitoring of LFTs every 4 weeks for
3 months and then 3 monthly thereafter. If the LFTs rise to more than 2–3 times
the upper limit of normal then the drug should be discontinued and LFTs closely
monitored to document resolution.
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Re-exposure to a drug implicated in DILI is not advisable, even at a reduced
dose as it may lead to a rapid and more severe relapse of DILI. In special
circumstances, a rechallenge may be warranted with close monitoring of LFTs if
the drug is considered essential.
++Specific drugs
Antibiotics (see Antibiotics)
Flucloxacillin is reported to cause severe hepatotoxicity in approximately 1 in
13,000 patients. This risk is increased at higher doses and for treatment longer
than 14 days. Liver dysfunction can occur any time between 1 week and 2
months after commencing therapy and up to 6 weeks after stopping. Deranged
LFTs typically show a mixed cholestatic and hepatitic profile, with cholestasis
and a mixed inflammatory infiltrate on histology. The course of cholestatic
hepatitis from flucloxacillin is often prolonged with persistently abnormal LFTs
for over 6 months in 10–30% of cases. These are associated with loss of smaller
bile ducts and peri-portal inflammation which may progress to biliary cirrhosis
and liver failure.
Tetracyclines may also be hepatotoxic, causing jaundice and acute fatty
infiltration. Minocycline is associated with two distinct forms of liver injury; an
acute hepatitis-like syndrome typically arising within 1–3 months of commencing
therapy and chronic hepatitis usually with autoimmune features which follows
long-term therapy. In both forms hypersensitivity features may be present with
rash, fever and eosinophilia. The liver injury is usually self-limiting with prompt
drug discontinuation, but if treatment is continued inadvertently, progressive
liver fibrosis and cirrhosis may develop.
Sulphonamides have been known to produce liver damage since their
development as antimicrobial agents. Most cases occur within 2–4 weeks
although the onset may be delayed several months. Hepatocellular injury with
marked increases in transaminases is often accompanied by hypersensitivity
features (rash and eosinophilia). Recovery may take several months.
Antifungals (see Antifungals)
Ketoconazole: this is the most hepatotoxic oral azole antifungal drug, due
to its extensive metabolism within the liver. Mild asymptomatic and transient
elevations (<2 times upper limit of normal) of transaminases have been estimated
to occur in up to 20% of patients, with clinically apparent hepatotoxicity
incidence in approximately 1 in 2000 and 1 in 15,000 users. The presentation is
usually with acute hepatitis any time between 1 and 6 months after starting the
drug. Recovery is usual within 3 months of drug discontinuation of the drug, but
acute fulminant hepatic failure requiring transplantation has been reported.
Itraconazole: this has been reported to cause asymptomatic rises in LFTs in
1–5% of patients. Biochemically the abnormalities are typically cholestatic but
hepatitic or mixed pictures can occur. LFTs generally return to normal within
3 months of discontinuing treatment. Reports of serious hepatotoxicity are
extremely rare.
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Fluconazole: transient mild to moderate elevations of serum
aminotransferases occur in up to 5% of patients treated with fluconazole. The
severity of liver injury ranges from transient asymptomatic enzyme elevations
in the majority to clinically apparent hepatitis and acute fatal liver failure in a
very small number of cases. The liver injury is typically hepatocellular, occurs
within the first few weeks of therapy and can be associated with a rash, fever
and eosinophilia. Complete resolution can take up to 4 months following drug
withdrawal.
With all the azoles, there are little data regarding cross-reactivity and
extreme caution should be applied when exposing patients who have had
hepatotoxicity to other agents in the same class.
Terbinafine: this has very rarely been associated with liver dysfunction. Liver
injury usually arises within the first 6 weeks of therapy. In a surveillance study
including over 25,000 patients there were only two reports of symptomatic
cholestatic liver injury. Asymptomatic elevations in hepatic enzymes were
recorded in less than 0.5% and in all cases, these normalized within 3–6 months
of discontinuation.
Azathioprine (see Azathioprine)
Azathioprine (AZA) therapy has been associated with several forms of
hepatotoxicity. Mild transient and asymptomatic rises in serum aminotransferase
levels are common during the first 3 months of therapy and resolve rapidly with
dose reduction or discontinuation. Acute cholestatic injury may occur within the
first year of therapy, and longer-term AZA may cause chronic hepatic damage
with nodular regenerative hyperplasia and portal hypertension. Baseline and
regular assessment of liver function is therefore required throughout treatment.
Corticosteroids (see Corticosteroids)
Corticosteroids can have major effects on the liver, particularly with long-term
or high dose therapy. Particular caution is needed in patients with pre-existing
liver disease.
Corticosteroid therapy can cause steatohepatitis, especially when given
in high doses for prolonged periods. Biochemical features include elevated
transaminases and liver histology demonstrates steatosis, hepatocyte ballooning
and an inflammatory infiltrate. These findings are usually reversible on dose
reduction or discontinuation. Pre-existing non-alcoholic steatohepatitis (NASH)
may be aggravated due to a combination of weight gain, insulin resistance and
altered lipid metabolism. Prolonged therapy increases the risk of fibrosis and
cirrhosis. Dose minimization and alternative drugs should be considered, with
monitoring for liver fibrosis in those on long-term treatment.
In patients who are hepatitis B virus (HBV) core antibody positive, high
dose steroids (e.g. prednisolone 60 mg daily or higher) can cause reactivation
of viral infection, resulting in an acute hepatitis and acute liver failure. Such
patients should be given prophylactic antiviral therapy with lamivudine 100 mg
once daily prior to commencing steroids. In patients with chronic HBV (i.e. HBV
surface antigen positive) oral corticosteroids are not contraindicated but advice
should be sought from a hepatologist as these drugs may increase the viral
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load (Table 1). Abnormal LFTs do not usually develop during treatment due to
­immunosuppressive effects, but on drug withdrawal an acute hepatitis may
occur, which may aggravate underlying liver damage and on rare instances,
precipitate acute liver failure.
TABLE 1 Hepatitis B virus (HBV) blood tests and their interpretation
Test
Interpretation of positive result
Hepatitis B surface antigen (HBsAg)
Acute or chronic infection with HBV
Hepatitis B surface antibody
Successful response to HBV vaccine or
recovery from acute HBV infection
Hepatitis B core antibody (HBcAb)
Past or present infection depending on
above test results
In patients with hepatitis C virus (HCV) infection, corticosteroid therapy
can lead to a rise in hepatitis C viral load, which may ultimately accelerate the
progression to hepatic fibrosis so close collaboration with a hepatologist is
advised to ensure appropriate monitoring.
Dapsone (see Dapsone)
Dapsone can cause an acute hepatitis and cholestatic jaundice. The onset
is usually sudden and associated with fever and a rash followed by jaundice,
and it occurs within a few days or weeks of starting treatment. Eosinophilia
is commonly seen. In rare instances dapsone DILI has led to acute liver failure;
however, most cases resolve within 2–4 weeks of drug discontinuation.
Methotrexate (see Methotrexate)
Short-term low to moderate dose treatment with methotrexate causes mild,
self-limiting elevation in the serum transaminases in about 15–50% of patients.
About 5% of patients develop more significantly elevated liver enzymes that
usually normalize rapidly with dose reduction or drug discontinuation. Folic
acid supplementation has been shown to be protective against this effect and is
routinely prescribed in conjunction with methotrexate.
Long-term methotrexate therapy is associated with development of dose
dependent hepatic fibrosis and this drug is therefore contraindicated in those
with underlying chronic liver disease, apart from in exceptional circumstances.
The risk and rate of progression to fibrosis or cirrhosis is increased in patients with
a heavy alcohol intake, those with diabetes, obesity, renal failure, age >60 years
and concomitant use of other potentially hepatotoxic drugs. These factors are
therefore considered to be relative contraindications to methotrexate therapy.
Nowadays, a pre-treatment liver biopsy to assess the degree of fibrosis is
only recommended in patients who are suspected clinically, biochemically or
radiologically to be at risk of, or to have underlying liver disease. If fibrosis
is confirmed then methotrexate is best avoided and an alternative therapy
considered.
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Significant fibrosis can occur in the context of entirely normal LFTs, which are
therefore unreliable in isolation for drug monitoring. A significant fibrosis risk is
associated with a cumulative dose of methotrexate exceeding 2.5 g. Historically,
due to the dose dependent development of hepatic fibrosis, guidelines have
recommended liver biopsy prior to commencement of therapy and after
a cumulative dose of 1, 3 and 8 grams. While liver biopsy remains the gold
standard for assessment of fibrosis, it carries a significant risk of morbidity and
is subject to sampling error.
Monitoring the blood level of the aminoterminal peptide of type III
pro-collagen (PIIINP) (a serological marker of hepatic fibrosis), has reduced the
need for routine liver biopsies. Patients with a persistently normal PIIINP levels
(measured 3 monthly) are very unlikely to have significant liver damage and
thus liver biopsies can be restricted to those with raised PIIINP levels.
Over the last decade other additional non-invasive methods to assess hepatic
fibrosis have become widely available. Transient elastography (FibroScan®) is a
rapid, immediate, cheap, non-invasive, reproducible and validated test that uses
ultrasound to measure liver stiffness gauged in kilopascals (kPa) as a marker of
fibrosis. It may help limit the need for biopsies, with the latter being reserved
for patients whose score is suggestive of moderate fibrosis (i.e. >7.1 kPa) or
where clinical suspicion/concern exists. At present a combination of transient
elastography in conjunction with PIIINP is likely to provide the ideal method for
monitoring of hepatic fibrosis and guiding the need for liver biopsy in patients
with psoriasis on methotrexate. The sensitivity and specificity of combining
these non-invasive markers of fibrosis need to be validated in future studies.
Long-term, low dose methotrexate therapy has also been implicated
in rare instances to cause reactivation of HBV in patients who are HBV core
antibody positive. However, the majority of the patients were also receiving
concomitant corticosteroids (see Corticosteroids). These cases have however, led
to recommendations that patients being commenced on methotrexate should
be tested for HBV surface antigen and HBV core antibody and, if positive,
consideration given to prophylaxis with antiviral agents.
Retinoids (see Acitretin and Isotretinoin)
Acitretin. Mild abnormalities in LFTs occur in up to one-third of patients taking
acitretin; however, only 1–5% of patients have abnormalities greater than three
times the upper limit of normal and require drug discontinuation. Clinically
apparent liver injury due to acitretin is rare, but several cases have been reported.
The time of onset is wide, ranging from 1 week to 9 months after commencing
therapy. The biochemical profile is typically of raised transaminases but
cholestatic hepatitis has been reported and may be accompanied by rash, fever
and eosinophilia. The vast majority of cases resolve on drug discontinuation.
Isotretinoin. Modest increases in serum aminotransferases occur in up to 15%
of patients taking isotretinoin, but fewer than 1% of patients have abnormalities
greater than three times the upper limit of normal. Clinically apparent liver
injury is exceedingly rare and acute liver injury with signs of hypersensitivity seen
with acitretin has not been reported. The serum aminotransferase elevation
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is self-limiting and often resolves without drug discontinuation. Isotretinoin is
contraindicated in patients with severely impaired liver function.
++Summary
In summary, the majority of systemic dermatological medications are safe. In
those known to be hepatotoxic, LFTs should be checked prior to commencement
and referral to a hepatologist for further investigations if abnormalities
detected. In patients with chronic liver disease the majority of drugs can be used,
but specific consideration should be given to dosing and monitoring. Systemic
drugs that are recognized to cause hepatotoxicity require LFT monitoring, with
cessation of the offending drug if LFTs become greater that 2–3 times the upper
limit of normal.
With acknowledgements to Jo Puleston and Julian Teare, authors of this chapter in the 1st edition.
++Further reading
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management
of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the
management and treatment of psoriasis with traditional systemic agents. J Am
Acad Dermatol 2009;61:451–85.
NICE Guideline on hepatitis B virus infection 2013. http://guidance.nice.org.uk/
CG165.
Perrillo RP. Reactivated hepatitis B due to medical interventions: the clinical
spectrum expands. Antivir Ther 2011;16(7):947–9.
Wolverton SE, Remlinger K. Suggested guidelines for patient monitoring:
hepatic and hematologic toxicity attributable to systemic dermatologic drugs.
Dermatol Clin 2007 Apr;25(2):195–205, vi–ii.
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Systemic Therapy &
Kidney Disease
Phil Mason
Many drugs and their metabolites are renally excreted and accumulate
in patients with chronic kidney disease (CKD), which may lead to increased
toxicity and side-effects. Kidney function decreases with age so otherwise
healthy elderly patients may have unrecognized CKD. It is therefore important
to identify such patients in order to modify dose or dosing frequency. This has
become easier with nearly universal reporting of an estimated glomerular
filtration rate (eGFR) alongside the creatinine measurement.
Other renal factors may be relevant, in particular heavy proteinuria,
hypoalbuminaemia and marked salt and water retention, which may change
drug pharmacokinetics (and pharmacodynamics). However, these rarely have a
significant effect on drug dosing.
++Identification of patients with impaired renal function
Table 1 indicates the prevalence of different degrees of CKD. Renal function
declines with age so that, for example, approximately 25% of men and
approximately 50% of women over the age of 75 years have an eGFR of less than
60 mL/min (CKD3). Although most of these will not progress to more severe
CKD (especially in the absence of proteinuria), the reduced GFR will affect drug
elimination.
TABLE 1 Prevalence of different stages of chronic kidney disease
Stage
GFR (mL/min/1.73 m2)
Prevalence in USA
1
>90
3.3%
2
60–89
3.0%
3
30–59
4.3%
4
15–29
0.2%
5
<15 (or dialysis/transplant)
0.1%
GFR: glomerular filtration rate.
Although data are from the USA, the prevalence is similar in other developed countries.
(from K/DOQI-NHANES III study)
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Precise measurement of the actual GFR using either radioactive isotopes or
iohexol is time consuming, expensive and neither practical nor necessary in
clinical practice. A creatinine clearance is a reliable surrogate of actual GFR but
requires an accurately collected 24-hour urine sample and blood creatinine,
making it unsuitable as a routine measurement. However, the GFR may be
estimated by a variety of formulae based on the serum creatinine, which is
dependent on renal function but also on muscle mass and dietary meat intake,
and can be affected by concurrent medication (Table 2). The method of estimating
renal function reported by all laboratories now uses the formula developed by
the Modification of Diet in Renal Disease Study Group (MDRD), which estimates
the GFR based on the patient’s age, sex, racial background and creatinine
(Table 3). It generally underestimates GFR when renal function is near normal
(>50 mL/min) but these patients tend not to need dose modification.
It should be remembered that that any estimate of GFR is only valid for
stable patients without an acute illness.
TABLE 2 Factors affecting creatinine levels
GFR
Muscle mass
Dietary meat intake
Hydration status
Drugs – direct, e.g. trimethoprim, cimetidine (interfere with renal tubular secretion of
creatinine)
NB: creatinine increased but GFR unaltered
Drugs – indirect, e.g. diuretics, which affect hydration status
Drugs which do affect GFR, e.g. NSAIDs or via interstitial nephritis, e.g. PPIs
GFR: glomerular filtration rate; NSAID: non-steroidal anti-inflammatory drug; PPI: proton pump inhibitor.
TABLE 3 Formulae for calculating estimates of kidney function: the Cockcroft–Gault
formula estimates a calculated creatinine clearance and the Modification
of Diet in Renal Disease (MDRD) estimates GFR
Cockcroft–Gault
MDRD
CrCl =
(140 – age) × wt (kg) × 1.23♂(1.04♀)
creatinine (µmol/L)
eGFR= 32788 × (creatinine, µmol/L) –1.154 × age –0.203
[× 1.212 if black] [× 0.742 if female]
GFR: glomerular filtration rate.
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Systemic Therapy & Kidney Disease
++Dosages for patients with CKD
Drug dose modification is rarely required until the eGFR falls below 60 mL/min
(CKD3) and most renally excreted drugs only need adjustment below 30 mL/min
(CKD4 and 5). Many drug Summary of Product Characteristics (SPCs) and the
British National Formulary (BNF) recommend dose modifications based on the
Cockcroft–Gault formula but the eGFR is a reasonable surrogate for this.
Before prescribing any drug in patients with CKD, the dosage should be
checked in the BNF. The Renal Drug Handbook provides comprehensive dose
recommendation for virtually all available drugs and also indicates whether
they are removed by different dialysis modalities. Pharmacists and renal units
are also available for advice.
++Nephrotoxic drugs
Some drugs have predictable dose related effects on kidney function (but
often of variable magnitude in different patients). These include, for example,
the calcineurin inhibitors tacrolimus and ciclosporin (cyclosporine), nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides. Other drugs
may have idiosyncratic effects, for instance drugs causing acute interstitial
nephritis. Currently proton pump inhibitors are the commonest culprits, but
others include antibiotics, mesalazine, allopurinol and diuretics. However, it is
important to remember these reactions are actually very rare.
++Drugs commonly used in dermatology
This is not an exhaustive list, and for patients with CKD it is important that the
correct dose of every prescribed drug be checked.
• Hydroxychloroquine and chloroquine: these drugs and their metabolites are
renally excreted so dose reduction is required and consideration should be given
to limiting the duration of treatment. They also increase levels of ciclosporin.
• Mepacrine: no dose reduction is necessary but renal function should be
monitored as idiosyncratic renal failure may develop.
• Antibiotics: most antibiotics do not need dose reduction but tetracycline
should be avoided, although doxycycline, minocycline and lymecycline are
safe. The macrolides are safe, but erythromycin doses need to be reduced
in dialysis patients and those with CKD5. They also inhibit cytochrome P450
(CYP450) 3A4 and increase calcineurin inhibitor levels.
• Retinoids: isotretinoin and acitretin are safe above a GFR of 10–15 mL/min
but at lower levels (and for patients on dialysis) the situation is unclear and
careful titration with monitoring is advised. They are reported to cause
glomerulonephritis and vasculitis, but this is very rare.
• Antiproliferative drugs: azathioprine and mycophenolate do not need
dose reduction but cyclophosphamide and especially methotrexate do.
Methotrexate is best avoided with eGFR <20 mL/min.
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Systemic Therapy & Kidney Disease
• Biologics: in general, no dose modifications are necessary but the SPCs
usually advise caution.
• Triazole antifungals: no dose reduction is required in CKD but they are
­potent CYP3A4 inhibitors and so drug interactions are common.
• Calcineurin inhibitors (tacrolimus and ciclosporin)There is no doubt that
these drugs are nephrotoxic. Patients with non-renal solid organ transplants
have a high incidence of developing CKD4–5 (6–21%) at 5 years posttransplant, with an estimated overall incidence of renal failure requiring
dialysis or transplantation of 1–1.5% per annum. Renal impairment is also a
recognized complication of their use in psoriasis. Higher levels are associated
with a higher incidence of CKD and, although some dermatological data
suggest that monitoring levels is not necessary, especially when used at
doses of 5 mg/kg or less, some patients will have high levels even at these
doses and a proportion of these will develop CKD. Monitoring of levels
should be considered especially in those at risk, soon after commencement
and regular creatinine measurements should be made for the duration of
treatment. It is important to warn the patient of potential interactions with
drugs (so that anyone prescribing is aware that the patient is on this drug)
foods and over-the-counter preparations (e.g. grapefruit juice, St. John’s
wort), which may increase drug levels. Any decline in renal function should
be investigated by referral to a nephrologist and a biopsy will usually be
performed to determine the cause.
++Drug prescription in dialysis & transplant patients
Dialysis patients should be considered to have an eGFR <10%, but it should
also be determined if the drug is removed by dialysis, and some drugs are best
administered at the end of a dialysis session. It is best to liaise with the renal
team involved before prescribing for this group of patients.
Transplant patients often have a degree of CKD but the main concern is
drug interactions that may affect levels of immunosuppressive drugs. Again, it
is best to liaise with the transplant team or transplant pharmacists.
With acknowledgements to Ruth Tarzi and Andrew Palmer, authors of this
chapter in the 1st edition.
++Further reading
Ashley C, Currie A. The Renal Drug Handbook. 3rd edn. Radcliffe Publishing
Ltd, 2008.
Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis.
Results of a multidose, double-blind trial. N Engl J Med 1991;324:277–84.
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Systemic Therapy & Kidney Disease
Feutren G, Abeywickrama K, Friend D, von Graffenried B. Renal function and
blood pressure in psoriatic patients treated with cyclosporin A. Br J Dermatol
1990;122(Suppl. 36):57–69.
Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a
nonrenal organ. N Engl J Med 2003;349:931–40.
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Appendix 1
Patient Health Questionnaire
for Depression (PHQ-9)
Over the last two weeks, how often have you been bothered by any of the following
problems?
Little interest or pleasure in doing things?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Feeling down, depressed, or hopeless?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Trouble falling or staying asleep, or sleeping too much?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Feeling tired or having little energy?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Poor appetite or overeating?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Feeling bad about yourself – or that you are a failure or
have let yourself or your family down?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Trouble concentrating on things, such as reading the
newspaper or watching television?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Moving or speaking so slowly that other people could have
noticed?
Or the opposite – being so fidgety or restless that you have
been moving around a lot more than usual?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
Thoughts that you would be better off dead, or of hurting
yourself in some way?
Not at all 0
Several days 1
More than half the days 2
Nearly every day 3
0 – not at all; 1 – several days; 2 – more than half the days; 3 – nearly every day.
The total score is then added. Minimum score = 0; maximum score = 27.
Depression Severity: 0–4 none, 5–9 mild, 10–14 moderate, 15–19 moderately severe,
20–27 severe.
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Appendix 2
Reading Chart for Use With Antimalarials
Use the texts below to test each eye separately with glasses when appropriate.
Record the smallest text that can be read at a distance most comfortable to the
patient.
N.5
He moved forward a few steps: the house was so dark behind him, the world so dim and uncertain in front
of him, that for a moment his heart failed him. He might have to search the whole garden for the dog.
N.6
The camp stood where, until quite lately, had been pasture and ploughland; the farm
house still stood in fold of the hill and had served us for battalion offices; ivy still supported
part of what had once been the walls of a fruit garden.
N.8
And another image came to me of an arctic hut and a trapper alone
with his furs and oil lamp and log fire; the remains of supper on the
table, a few books.
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Appendix 3
Example of Consent Form to Opt Out of
the Mandatory Pregnancy Prevention
Programme
I have received the information about the risks of having an affected baby
if I should become pregnant while taking isotretinoin.
I am aware that this risk to a pregnancy persists throughout the duration
of the treatment with isotretinoin and during the month after finishing
treatment.
I believe that I am not pregnant at this moment.
I believe that I am not at risk of becoming pregnant during the course of
treatment with isotretinoin or in the month following treatment.
I have discussed with ...................... (name of doctor or nurse) the risks to
a pregnancy during treatment with isotretinoin and accept these risks if I
take isotretinoin.
I am prepared to take isotretinoin without taking/using contraception at
the same time.
If I become pregnant while taking isotretinoin or in the month after
treatment, I will inform ...................... and seek advice from .......................
Signed: ______________________ Date: _________________
Print Name: __________________________________________
Witnessed: ___________________________________________
Declaration: __________________________________________
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Appendix 4
Dermatology Life Quality Index (DLQI)
Hospital No:...............
Date:..............
Name:..............Score:..............
Address:..............
Diagnosis:..............
The aim of this questionnaire is to measure how much your skin problem has
affected your life OVER THE LAST WEEK. Please tick r one box for each question.
1.
Over the last week, how itchy, sore,
painful or stinging has your skin
been?
Very much
A lot
A little
Not at all
r
r
r
r
2.
Over the last week, how
embarrassed or self conscious have
you been because of your skin?
Very much
A lot
A little
Not at all
r
r
r
r
3.
Over the last week, how much has
your skin interfered with you going
shopping or looking after your home
or garden?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
Over the last week, how much has
your skin influenced the clothes
you wear?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
5.
Over the last week, how much has
your skin affected any social or
leisure activities?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
6.
Over the last week, how much has
your skin made it difficult for you to
do any sport?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
4.
Cont...
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Dermatology Life Quality Index (DLQI)
7.
8.
9.
10.
Appendix 4
Over the last week, has your skin
prevented you from working or
studying?
Yes
No
r
r
If “No”, over the last week how much
has your skin been a problem at work
or studying?
A lot
A little
Not at all
r
r
r
r
Over the last week, how much has
your skin created problems with your
partner or any of your close friends
or relatives?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
Over the last week, how much
has your skin caused any sexual
difficulties?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
Over the last week, how much of a
problem has the treatment for your
skin been, for example by making
your home messy, or by taking
up time?
Very much
A lot
A little
Not at all
r
r
r
r
Not relevant r
Not relevant r
Please check you have answered EVERY question. Thank you.
© AY Finlay, GK Khan, April 1992
For permission to use the DLQI, contact dermqol@cf.ac.uk.
More information at www.dermatology.org.uk.
Scoring: 0 – not at all; 1 – a little; 2 – a lot; 3 – very much. Minimum score =
0; maximum score = 30.
Score Analysis: 0–1 = no effect at all on patient's life; 2–5 = small effect on
patient's life; 6–10 = moderate effect on patient's life; 11–20 = very large
effect on patient's life; 21–30 = extremely large effect on patient's life.
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HANDBOOK OF
MEDICINE
The Handbook of Systemic Drug Treatment in Dermatology helps
prescribers and patients make rational decisions about drug treatment
while considering known risks and potential unwanted effects.
Presented in a concise and reader-friendly format, this valuable reference is of practical use for dermatologists at all stages in their careers
as well as specialist nurse practitioners and family practitioners who
share the care of patients being administered systemic dermatological
therapy. It can also be helpful to those in allied specialties such as
rheumatology, gastroenterology, and ophthalmology.
SYSTEMIC DRUG
TREATMENT IN
DERMATOLOGY
S E C O N D
E D I T I O N
This second edition includes new drugs as well as information on new
guidelines for prescribing and monitoring established drugs.
Edited by
Sarah H Wakelin, BSc, MB BS, FRCP, Consultant Dermatologist,
St. Mary’s Hospital, Imperial College Healthcare Trust, and Honorary
Senior Lecturer, Imperial College London, London, UK
Howard I Maibach, MD, Professor, Department of Dermatology,
University of California, San Francisco, San Francisco, CA, USA
Clive B Archer, BSc, MB BS, MSc Med Ed, MD (Lond), PhD, FRCP (Edin,
Glasg, Lond), Consultant Dermatologist, St John’s Institute of Dermatology, Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, and
Visiting Senior Lecturer in Pharmacology, Institute of Pharmaceutical
Science, King’s College London, London, UK
K22298
ISBN: 978-1-4822-2284-5
90000
Sarah H Wakelin | Howard I Maibach | Clive B Archer
9 781482 222845
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